rs147157552

chr5-128527886-G-Achr5-128527886-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_001999.4(FBN2):c.518C>T(p.Thr173Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00128 in 1,608,094 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 4.49

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001999.4
• PP2: Missense variant where missense usually causes diseases, FBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.017662913).
• BP6: Variant 5-128527886-G-A is Benign according to our data. Variant chr5-128527886-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 155796.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=10, Uncertain_significance=2}. Variant chr5-128527886-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00108 (165/152250) while in subpopulation NFE AF= 0.00194 (132/68008). AF 95% confidence interval is 0.00167. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 165 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.518C>T	p.Thr173Ile	missense_variant	4/65	ENST00000262464.9
FBN2	XM_017009228.3	c.518C>T	p.Thr173Ile	missense_variant	4/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.518C>T	p.Thr173Ile	missense_variant	4/65	1	NM_001999.4	P1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00116 AC: 292 AN: 250682 Hom.: 0 AF XY: 0.00125 AC XY: 169 AN XY: 135494

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00198

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00130 AC: 1898 AN: 1455844 Hom.: 3 Cov.: 29 AF XY: 0.00134 AC XY: 969 AN XY: 724632

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.000718

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00109

Gnomad4 NFE exome AF: 0.00153

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74448

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.00104

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00135 AC: 164

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00186

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	FBN2: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 27, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 12, 2014	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 30, 2015	Variant classified as Uncertain Significance - Favor Benign. The p.Thr173Ile var iant in FBN2 has not been previously reported in individuals with connective tis sue disorders. It has been identified in 0.2% (146/65724) of European chromosom es, including 1 homozygous individual, by the Exome Aggregation Consortium (ExAC , http://exac.broadinstitute.org; dbSNP rs147157552). Computational prediction t ools and conservation analysis suggest that this variant may not impact the prot ein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the p.Thr173Ile variant is uncer tain, its frequency and lack of conservation suggests that it is more likely to be benign. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 29, 2017	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Blueprint Genetics	May 19, 2014	- -

Congenital contractural arachnodactyly Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

Connective tissue disorder Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jun 20, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

FBN2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 01, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.;D;T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;.;.;D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.018	T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.4	L;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D;.;D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.045	D;.;D;D;T
Polyphen		0.047	B;.;B;B;B
Vest4		0.38
MVP		0.35
MPC		0.53
ClinPred		0.029	T
GERP RS		3.2
Varity_R		0.096
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs147157552; hg19: chr5-127863579;