rs12460643

Variant names:

• chr19-8087841-A-G
• rs12460643
• NM_032447.5:c.6603T>C

Your query was ambiguous. Multiple possible variants found:

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

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.6603T>C​(p.Asp2201Asp) 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
• 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=-0.66).
• BP6: Variant 19-8087841-A-G is Benign according to our data. Variant chr19-8087841-A-G is described in ClinVar as Benign. ClinVar VariationId is 1603105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032447.5. 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
	FBN3	NM_032447.5	MANE Select	c.6603T>C	p.Asp2201Asp	synonymous	Exon 53 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.6603T>C	p.Asp2201Asp	synonymous	Exon 53 of 64	NP_001308360.1	Q75N90

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN3	ENST00000600128.6	TSL:1 MANE Select	c.6603T>C	p.Asp2201Asp	synonymous	Exon 53 of 64	ENSP00000470498.1	Q75N90
	FBN3	ENST00000270509.6	TSL:1	c.6603T>C	p.Asp2201Asp	synonymous	Exon 52 of 63	ENSP00000270509.2	Q75N90
	FBN3	ENST00000601739.5	TSL:1	c.6603T>C	p.Asp2201Asp	synonymous	Exon 53 of 64	ENSP00000472324.1	Q75N90

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

GnomAD2 exomes AF: 0.681 AC: 171020 AN: 251266 AF XY: 0.677

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 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

African (AFR) AF: 0.908 AC: 30386 AN: 33476

American (AMR) AF: 0.655 AC: 29290 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.728 AC: 19020 AN: 26134

East Asian (EAS) AF: 0.493 AC: 19589 AN: 39696

South Asian (SAS) AF: 0.569 AC: 49047 AN: 86256

European-Finnish (FIN) AF: 0.654 AC: 34905 AN: 53386

Middle Eastern (MID) AF: 0.718 AC: 4135 AN: 5758

European-Non Finnish (NFE) AF: 0.722 AC: 802233 AN: 1111664

Other (OTH) AF: 0.711 AC: 42961 AN: 60382

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

African (AFR) AF: 0.902 AC: 37451 AN: 41512

American (AMR) AF: 0.709 AC: 10821 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 2545 AN: 3470

East Asian (EAS) AF: 0.494 AC: 2539 AN: 5138

South Asian (SAS) AF: 0.522 AC: 2516 AN: 4816

European-Finnish (FIN) AF: 0.646 AC: 6809 AN: 10540

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.722 AC: 49081 AN: 67938

Other (OTH) AF: 0.758 AC: 1603 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.089
DANN	Benign	0.54
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism (auto)

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