rs7257948

Variant names:

• chr19-8073170-C-A
• rs7257948
• NM_032447.5:c.7830G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032447.5(FBN3):​c.7830G>T​(p.Glu2610Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.555 in 1,613,530 control chromosomes in the GnomAD database, including 254,989 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (32164 hom., cov: 32)
  • Exomes 𝑓: 0.55 (222825 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.13
• Publications: 33 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.964196E-6).
• BP6: Variant 19-8073170-C-A is Benign according to our data. Variant chr19-8073170-C-A is described in ClinVar as Benign. ClinVar VariationId is 1669122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.847 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.7830G>T	p.Glu2610Asp	missense	Exon 62 of 64	NP_115823.3
	FBN3	NM_001321431.2		c.7830G>T	p.Glu2610Asp	missense	Exon 62 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.7830G>T	p.Glu2610Asp	missense	Exon 62 of 64	ENSP00000470498.1	Q75N90
	FBN3	ENST00000270509.6	TSL:1	c.7830G>T	p.Glu2610Asp	missense	Exon 61 of 63	ENSP00000270509.2	Q75N90
	FBN3	ENST00000601739.5	TSL:1	c.7830G>T	p.Glu2610Asp	missense	Exon 62 of 64	ENSP00000472324.1	Q75N90

Frequencies

GnomAD3 genomes AF: 0.633 AC: 96149 AN: 151890 Hom.: 32116 Cov.: 32

Gnomad AFR AF: 0.855

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.589

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.557

Gnomad OTH AF: 0.609

GnomAD2 exomes AF: 0.543 AC: 135728 AN: 250018 AF XY: 0.531

Gnomad AFR exome AF: 0.862

Gnomad AMR exome AF: 0.590

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.384

Gnomad FIN exome AF: 0.594

Gnomad NFE exome AF: 0.552

Gnomad OTH exome AF: 0.536

GnomAD4 exome AF: 0.547 AC: 799403 AN: 1461522 Hom.: 222825 Cov.: 56 AF XY: 0.541 AC XY: 393470 AN XY: 727086

African (AFR) AF: 0.863 AC: 28895 AN: 33480

American (AMR) AF: 0.598 AC: 26757 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.423 AC: 11059 AN: 26128

East Asian (EAS) AF: 0.399 AC: 15823 AN: 39696

South Asian (SAS) AF: 0.395 AC: 34077 AN: 86256

European-Finnish (FIN) AF: 0.591 AC: 31487 AN: 53234

Middle Eastern (MID) AF: 0.458 AC: 2638 AN: 5766

European-Non Finnish (NFE) AF: 0.554 AC: 616197 AN: 1111866

Other (OTH) AF: 0.538 AC: 32470 AN: 60388

GnomAD4 genome AF: 0.633 AC: 96263 AN: 152008 Hom.: 32164 Cov.: 32 AF XY: 0.630 AC XY: 46800 AN XY: 74302

African (AFR) AF: 0.854 AC: 35452 AN: 41496

American (AMR) AF: 0.619 AC: 9452 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1465 AN: 3470

East Asian (EAS) AF: 0.379 AC: 1949 AN: 5144

South Asian (SAS) AF: 0.393 AC: 1894 AN: 4814

European-Finnish (FIN) AF: 0.589 AC: 6222 AN: 10572

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.557 AC: 37839 AN: 67938

Other (OTH) AF: 0.610 AC: 1284 AN: 2106

Alfa AF: 0.569 Hom.: 102235

Bravo AF: 0.646

TwinsUK AF: 0.558 AC: 2070

ALSPAC AF: 0.532 AC: 2052

ESP6500AA AF: 0.845 AC: 3725

ESP6500EA AF: 0.540 AC: 4648

ExAC AF: 0.546 AC: 66232

Asia WGS AF: 0.446 AC: 1551 AN: 3478

EpiCase AF: 0.539

EpiControl AF: 0.536

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
AlphaMissense	Benign	0.026
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.0050
DANN	Benign	0.14
DEOGEN2	Benign	0.015	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0000020	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.7	N
PhyloP100		-1.1
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.41		Loss of catalytic residue at E2610 (P = 0.2439)
MPC		0.17
ClinPred		0.0087	T
GERP RS		-3.8
Varity_R		0.075
gMVP		0.74
Mutation Taster		=99/1	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: rs7257948; hg19: chr19-8138054; COSMIC: COSV54462305; COSMIC: COSV54462305;