19-8131624-G-C

Variant names:

• chr19-8131624-G-C
• rs12974280
• NM_032447.5:c.1920C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032447.5(FBN3):​c.1920C>G​(p.Ser640Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 1,613,934 control chromosomes in the GnomAD database, including 101,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (7007 hom., cov: 33)
  • Exomes 𝑓: 0.35 (94138 hom.)
• Consequence: FBN3 NM_032447.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.09
• Publications: 16 publications found

Genes affected

FBN3 (HGNC:18794): (fibrillin 3) This gene encodes a memebr of the fibrillin protein family. Fibrillins are extracellular matrix molecules that assemble into microfibrils in many connective tissues. This gene is most highly expressed in fetal tissues and its protein product is localized to extracellular microfibrils of developing skeletal elements, skin, lung, kidney, and skeletal muscle. This gene is potentially involved in Weill-Marchesani syndrome. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-8131624-G-C is Benign according to our data. Variant chr19-8131624-G-C is described in ClinVar as [Benign]. Clinvar id is 1600060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5	c.1920C>G	p.Ser640Ser	synonymous_variant	Exon 15 of 64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.1920C>G	p.Ser640Ser	synonymous_variant	Exon 15 of 64	1	NM_032447.5	ENSP00000470498.1
FBN3	ENST00000270509.6	c.1920C>G	p.Ser640Ser	synonymous_variant	Exon 14 of 63	1		ENSP00000270509.2
FBN3	ENST00000601739.5	c.1920C>G	p.Ser640Ser	synonymous_variant	Exon 15 of 64	1		ENSP00000472324.1
FBN3	ENST00000651877.1	c.2046C>G	p.Ser682Ser	synonymous_variant	Exon 15 of 64			ENSP00000498507.1

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42710 AN: 152100 Hom.: 7008 Cov.: 33

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.0517

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.300

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.386

Gnomad OTH AF: 0.307

GnomAD2 exomes AF: 0.291 AC: 73104 AN: 250978 AF XY: 0.299

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.388

Gnomad EAS exome AF: 0.0506

Gnomad FIN exome AF: 0.308

Gnomad NFE exome AF: 0.390

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.349 AC: 509848 AN: 1461716 Hom.: 94138 Cov.: 62 AF XY: 0.347 AC XY: 252525 AN XY: 727136

African (AFR) AF: 0.136 AC: 4541 AN: 33480

American (AMR) AF: 0.182 AC: 8119 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 10162 AN: 26136

East Asian (EAS) AF: 0.0518 AC: 2055 AN: 39698

South Asian (SAS) AF: 0.235 AC: 20248 AN: 86236

European-Finnish (FIN) AF: 0.316 AC: 16854 AN: 53406

Middle Eastern (MID) AF: 0.372 AC: 2144 AN: 5768

European-Non Finnish (NFE) AF: 0.383 AC: 425403 AN: 1111894

Other (OTH) AF: 0.337 AC: 20322 AN: 60382

GnomAD4 genome AF: 0.281 AC: 42704 AN: 152218 Hom.: 7007 Cov.: 33 AF XY: 0.274 AC XY: 20399 AN XY: 74410

African (AFR) AF: 0.140 AC: 5830 AN: 41560

American (AMR) AF: 0.244 AC: 3735 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 1391 AN: 3472

East Asian (EAS) AF: 0.0517 AC: 267 AN: 5168

South Asian (SAS) AF: 0.214 AC: 1031 AN: 4824

European-Finnish (FIN) AF: 0.300 AC: 3180 AN: 10592

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.386 AC: 26229 AN: 67996

Other (OTH) AF: 0.306 AC: 646 AN: 2114

Alfa AF: 0.327 Hom.: 2818

Bravo AF: 0.271

Asia WGS AF: 0.145 AC: 503 AN: 3478

EpiCase AF: 0.397

EpiControl AF: 0.391

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

FBN3-related disorder Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.027
DANN	Benign	0.37
PhyloP100		-4.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs12974280; hg19: chr19-8196508; COSMIC: COSV54453386;