rs779913610

Variant names:

• chr15-48481683-G-A
• rs779913610
• NM_000138.5:c.3936C>T

Your query was ambiguous. Multiple possible variants found:

• chr15-48481683-G-A
• chr15-48481683-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000138.5(FBN1):​c.3936C>T​(p.Ser1312Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,613,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1312S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: FBN1 NM_000138.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:11
• Conservation: PhyloP100: -0.851
• Publications: 1 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):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, G2P, PanelApp Australia, Orphanet, Ambry Genetics
• Acromicric dysplasia

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

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

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 15-48481683-G-A is Benign according to our data. Variant chr15-48481683-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 237089.
• BP7: Synonymous conserved (PhyloP=-0.851 with no splicing effect.

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.3936C>T	p.Ser1312Ser	synonymous	Exon 32 of 66	NP_000129.3
	FBN1	NM_001406716.1		c.3936C>T	p.Ser1312Ser	synonymous	Exon 31 of 65	NP_001393645.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.3936C>T	p.Ser1312Ser	synonymous	Exon 32 of 66	ENSP00000325527.5
	FBN1	ENST00000559133.6	TSL:1	n.3936C>T		non_coding_transcript_exon	Exon 32 of 67	ENSP00000453958.2
	FBN1	ENST00000674301.2		n.3936C>T		non_coding_transcript_exon	Exon 32 of 68	ENSP00000501333.2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151654 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000191 AC: 48 AN: 251196 AF XY: 0.000177

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000211 AC: 309 AN: 1461430 Hom.: 0 Cov.: 30 AF XY: 0.000217 AC XY: 158 AN XY: 727024

African (AFR) AF: 0.000149 AC: 5 AN: 33448

American (AMR) AF: 0.000134 AC: 6 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26124

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39678

South Asian (SAS) AF: 0.000406 AC: 35 AN: 86228

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000206 AC: 229 AN: 1111686

Other (OTH) AF: 0.000166 AC: 10 AN: 60378

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151772 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74148

African (AFR) AF: 0.0000242 AC: 1 AN: 41386

American (AMR) AF: 0.000197 AC: 3 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5168

South Asian (SAS) AF: 0.000626 AC: 3 AN: 4796

European-Finnish (FIN) AF: 0.000192 AC: 2 AN: 10436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000177 AC: 12 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000146 Hom.: 0

Bravo AF: 0.000178

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Familial thoracic aortic aneurysm and aortic dissection (3)
-	1	1	Marfan syndrome (2)
-	-	1	Acromicric dysplasia (1)
-	-	1	Ectopia lentis 1, isolated, autosomal dominant (1)
-	-	1	Geleophysic dysplasia (1)
-	-	1	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Stiff skin syndrome (1)
-	-	1	Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.51
PhyloP100		-0.85
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs779913610; hg19: chr15-48773880;