rs12460643

Positions:

• chr19-8087841-A-G
• chr19-8087841-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032447.5(FBN3):​c.6603T>C​(p.Asp2201=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 1,613,476 control chromosomes in the GnomAD database, including 411,406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (43759 hom., cov: 31)
  • Exomes 𝑓: 0.71 (367647 hom.)
• Consequence: FBN3 NM_032447.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.492

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-8087841-A-G is Benign according to our data. Variant chr19-8087841-A-G is described in ClinVar as [Benign]. Clinvar id is 1603105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-8087841-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.492 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.895 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN3	NM_032447.5	c.6603T>C	p.Asp2201=	synonymous_variant	53/64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.6603T>C	p.Asp2201=	synonymous_variant	53/64	1	NM_032447.5	ENSP00000470498

Frequencies

GnomAD3 genomes AF: 0.751 AC: 114034 AN: 151884 Hom.: 43698 Cov.: 31

Gnomad AFR AF: 0.902

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.733

Gnomad EAS AF: 0.495

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.646

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.722

Gnomad OTH AF: 0.765

GnomAD3 exomes AF: 0.681 AC: 171020 AN: 251266 Hom.: 59494 AF XY: 0.677 AC XY: 91985 AN XY: 135806

Gnomad AFR exome AF: 0.906

Gnomad AMR exome AF: 0.644

Gnomad ASJ exome AF: 0.724

Gnomad EAS exome AF: 0.509

Gnomad SAS exome AF: 0.564

Gnomad FIN exome AF: 0.653

Gnomad NFE exome AF: 0.719

Gnomad OTH exome AF: 0.696

GnomAD4 exome AF: 0.706 AC: 1031566 AN: 1461474 Hom.: 367647 Cov.: 44 AF XY: 0.702 AC XY: 510257 AN XY: 727080

Gnomad4 AFR exome AF: 0.908

Gnomad4 AMR exome AF: 0.655

Gnomad4 ASJ exome AF: 0.728

Gnomad4 EAS exome AF: 0.493

Gnomad4 SAS exome AF: 0.569

Gnomad4 FIN exome AF: 0.654

Gnomad4 NFE exome AF: 0.722

Gnomad4 OTH exome AF: 0.711

GnomAD4 genome AF: 0.751 AC: 114143 AN: 152002 Hom.: 43759 Cov.: 31 AF XY: 0.741 AC XY: 55050 AN XY: 74268

Gnomad4 AFR AF: 0.902

Gnomad4 AMR AF: 0.709

Gnomad4 ASJ AF: 0.733

Gnomad4 EAS AF: 0.494

Gnomad4 SAS AF: 0.522

Gnomad4 FIN AF: 0.646

Gnomad4 NFE AF: 0.722

Gnomad4 OTH AF: 0.758

Alfa AF: 0.750 Hom.: 19127

Bravo AF: 0.769

Asia WGS AF: 0.530 AC: 1844 AN: 3478

EpiCase AF: 0.726

EpiControl AF: 0.728

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.089
DANN	Benign	0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs12460643; hg19: chr19-8152725; COSMIC: COSV54462957;