rs111801777

Variant names:

• chr15-48489875-T-C
• rs111801777
• NM_000138.5:c.3058A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-48489875-T-C
• chr15-48489875-T-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP2 BP5 BS1

This summary comes from the ClinGen Evidence Repository: The NM_000138 c.3058A>G, is a missense variant in FBN1 predicted to cause a substitution of a Threonine by Alanine at amino acid 1020 (p.Thr1020Ala). This variant was found in 12 probands with variable phenotypes, mostly thoracic aortic aneurysm or a marfanoid habitus. One proband additionally presented ectopia lentis. Two of these probands carried two other pathogenic variants: a variant in FBN1 (BP2) and a variant in TGFBR1 (BP5). The variant in FBN1 has been reported ten times in ClinVar: 8 times as likely benign and two times as a variant of uncertain significance (Variation ID: 42325). The variant has been reported in the literature in multiple affected individuals including one individual with classical Marfan syndrome (PMID:11175294), one individual with incomplete Marfan syndrome (PMID:18435798), one patient with MASS syndrome (PMID:25944730), and an individual with bicuspid aortic valve and aortic root aneurysm (PMID:28387797). This variant has also been reported in 3 patients with Lujan-Fryns syndrome (PMID:19293843, PMID:28027854), including two brothers with marfanoid habitus, learning disabilities without cardiac defects (PMID:28027854). These brothers also share a variant in MECP2. Segregation analysis in one family showed that the variant was also present in four additional family members, none of which had aortic aneurysm, two had a marfanoid habitus This variant has been identified in 80 individuals of European-non-Finnish origin (MAF: 0.062%) in gnomad v2.1.1 (https://gnomad.broadinstitute.org/) (BS1). The constraint z-score for missense variants affecting FBN1 is 5.06, however due to the presence of benign arguments PP2 cannot be used. In summary, this variant meets criteria to be classified as likely benign for Marfan syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen FBN1 VCEP: BS1, BP2, BP5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA013721/MONDO:0007947/022

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: FBN1 NM_000138.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:14
• Conservation: PhyloP100: 1.49
• Publications: 14 publications found

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

FBN1 Gene-Disease associations (from GenCC):

• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Genomics England PanelApp
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Weill-Marchesani syndrome 2, dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal Marfan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ectopia lentis 1, isolated, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• Shprintzen-Goldberg syndrome

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000138.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.3058A>G	p.Thr1020Ala	missense	Exon 25 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.3058A>G	p.Thr1020Ala	missense	Exon 24 of 65	NP_001393645.1	P35555

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.3058A>G	p.Thr1020Ala	missense	Exon 25 of 66	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.3058A>G		non_coding_transcript_exon	Exon 25 of 67	ENSP00000453958.2	H0YND0
	FBN1	ENST00000674301.2		n.3058A>G		non_coding_transcript_exon	Exon 25 of 68	ENSP00000501333.2	A0A6I8PL22

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000454 AC: 114 AN: 251294 AF XY: 0.000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.000625

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000330 AC: 482 AN: 1461856 Hom.: 1 Cov.: 31 AF XY: 0.000355 AC XY: 258 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86258

European-Finnish (FIN) AF: 0.000506 AC: 27 AN: 53404

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.000303 AC: 337 AN: 1111992

Other (OTH) AF: 0.000513 AC: 31 AN: 60394

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152322 Hom.: 0 Cov.: 31 AF XY: 0.000322 AC XY: 24 AN XY: 74472

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.000457 AC: 7 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68038

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000414 Hom.: 1

Bravo AF: 0.000325

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	4	Marfan syndrome (5)
-	2	2	not provided (4)
-	-	3	Familial thoracic aortic aneurysm and aortic dissection (3)
-	-	3	not specified (3)
-	-	1	FBN1-related disorder (1)
-	-	1	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	0.99
Eigen	Benign	-0.18
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.69	T
PhyloP100		1.5
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.52	N
REVEL	Uncertain	0.39
Sift	Benign	0.042	D
Sift4G	Benign	0.20	T
Vest4		0.11
MVP		0.98
MPC		0.49
ClinPred		0.018	T
GERP RS		5.7
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs111801777; hg19: chr15-48782072;