rs61746008

chr15-48412619-G-Achr15-48412619-G-C

• Frequency:
  • Genomes: 𝑓 0.00071 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (1 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Conflicting interpretations of pathogenicity criteria provided, conflicting interpretations U:5 B:19
• Conservation: PhyloP100: 2.13

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, FBN1
• BP4: Computational evidence support a benign effect (MetaRNN=0.04389882).
• BP6: Variant 15-48412619-G-A is Benign according to our data. Variant chr15-48412619-G-A is described in ClinVar as [Conflicting_interpretations_of_pathogenicity]. Clinvar id is 16445. Status of the report is criteria_provided_conflicting_interpretations, 1 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=19, Uncertain_significance=3}. Variant chr15-48412619-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected. gnomad allele frequency = 0.00071 (108/152166) while in subpopulation AMR AF= 0.00209 (32/15278). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad. There are 49 alleles in male gnomad subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 108 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN1	NM_000138.5	c.8176C>T	p.Arg2726Trp	missense_variant	65/66	ENST00000316623.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN1	ENST00000316623.10	c.8176C>T	p.Arg2726Trp	missense_variant	65/66	1	NM_000138.5	P1

Frequencies

GnomAD3 genomes AF: 0.000710 AC: 108 AN: 152166 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000728 AC: 183 AN: 251466 Hom.: 1 AF XY: 0.000751 AC XY: 102 AN XY: 135906

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000888

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000761 AC: 1113 AN: 1461880 Hom.: 2 AF XY: 0.000758 AC XY: 551 AN XY: 727240

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000871

Gnomad4 OTH exome AF: 0.000729

Alfa AF: 0.000872 Hom.: 0

Bravo AF: 0.000778

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000733 AC: 89

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting interpretations of pathogenicity

Submissions summary: Uncertain:5Benign:19

Revision: criteria provided, conflicting interpretations

LINK:

Submissions by phenotype

Marfan syndrome Uncertain:4Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with FBN1-related disease. Variants predicted to result in nonsense mediated decay cause loss of function effects, and are more commonly associated with severe Marfan syndrome (MIM#154700). Missense variants with both dominant negative and loss of function effects on protein function, are associated with Marfan syndrome and ectopia lentis (MIM#129600) (OMIM, PMID: 29357934). The exact genotype-phenotype correlation for this gene is still unclear, and is compounded by variable expressivity (PMID: 20301510). (I) 0107 - This gene is predominantly associated with autosomal dominant disease; autosomal recessive forms of Marfan syndrome have been reported infrequently (PMID: 27274304; 31950671). 0115 - Variants in this gene are known to have variable expressivity. The genotype-phenotype correlations for this gene are unclear, with single variants reported in patients with a range of phenotypes (PMID: 20301510, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of DISEASE. (SB) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3: 12 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Arg2726Leu) and p.(Arg2726Gln) have been reported VUS in ClinVar, but p.(Arg2726Gln) has also been regarded likely benign (PMID: 31227806). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported both as VUS and likely benign in ClinVar and it used to be known as a Marfanoid Skeletal Syndrome variant, as it has mostly been detected in individuals without cardiac and ocular manifestations (OMIM). More recently, even though some consider it causative with incomplete penetrance (PMID: 26875674), others see it as a likely benign variant (PMID: 31227806). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Studies have shown that it affects the conversion mediated of profibrillin to fibrillin (PMIDs: 26875674, 7738200). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Dec 01, 2015	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 01, 2009	- -
Uncertain significance, no assertion criteria provided	clinical testing	Center for Medical Genetics Ghent, University of Ghent	Nov 07, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as causing Marfanoid-like features. It has been found 13 times in our laboratory, always inherited when parents are tested, and not always in patients with Marfanoid features. -
Uncertain significance, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Apr 19, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 28, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	Criteria applied: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2023	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 08, 2023	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 25, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 28, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Nov 20, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 04, 2019	Variant summary: FBN1 c.8176C>T (p.Arg2726Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 252730 control chromosomes, predominantly at a frequency of 0.0017 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.8176C>T has been reported in the literature in individuals affected with Marfan Syndrome, as well as in mildly affected and unaffected family members, suggesting incomplete penetrance, or a mostly benign nature. Since the penetrance of Marfan Syndrome (0.71) due to this variant appears to be lower than expected (0.8), no conclusions can be drawn from these data. Co-occurrences with other pathogenic FBN1 variants have been reported (e.g. Stheneur 2009: c.3299G>T (p.Gly1100V), c.6388G>A (p.Glu2130Lys), c.1416C>A (p.Cys472X); Arnaud 2017: c.1585C>T (Arg529X), c.6388G>A (p.Glu2130Lys); Becerra-Munoz 2018: c.7754T>C, (p.Ile2585Thr); and in an internal sample: c.3073_3074insA (p.Phe1025fsX7)), providing supporting evidence for a benign role. Some publications also reported experimental evidence evaluating an impact on protein function, showing a decreased protein processing (C-terminal propeptide cleavage) (Milewicz 1995, Lonnqvist 1998). Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (4x) and likely benign (6x). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, PreventionGenetics	-	- -

Stiff skin syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 28, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Weill-Marchesani syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 28, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Geleophysic dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 28, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Acromicric dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 28, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

- -

Ectopia lentis 1, isolated, autosomal dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Nov 28, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.084

T

BayesDel_noAF

Uncertain

0.090

Cadd

Uncertain

24

Dann

Uncertain

1.0

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.95

D

LIST_S2

Pathogenic

0.98

D

M_CAP

Benign

0.084

D

MetaRNN

Benign

0.044

T

MetaSVM

Benign

-0.35

T

MutationTaster

Benign

0.99

D

PrimateAI

Uncertain

0.72

T

PROVEAN

Pathogenic

-4.7

D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

D

Sift4G

Uncertain

0.0030

D

Vest4

0.60

MVP

0.95

MPC

1.3

ClinPred

0.071

T

GERP RS

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61746008; hg19: chr15-48704816;