rs7257948

chr19-8073170-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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, single submitter B:1
• Conservation: PhyloP100: -1.13

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 -14 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 id is 1669122.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-8073170-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN3	NM_032447.5	c.7830G>T	p.Glu2610Asp	missense_variant	62/64	ENST00000600128.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN3	ENST00000600128.6	c.7830G>T	p.Glu2610Asp	missense_variant	62/64	1	NM_032447.5
FBN3	ENST00000270509.6	c.7830G>T	p.Glu2610Asp	missense_variant	61/63	1
FBN3	ENST00000601739.5	c.7830G>T	p.Glu2610Asp	missense_variant	62/64	1
FBN3	ENST00000651877.1	c.7956G>T	p.Glu2652Asp	missense_variant	62/64			P1

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

GnomAD3 exomes AF: 0.543 AC: 135728 AN: 250018 Hom.: 38610 AF XY: 0.531 AC XY: 71883 AN XY: 135430

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 SAS exome AF: 0.390

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

Gnomad4 AFR exome AF: 0.863

Gnomad4 AMR exome AF: 0.598

Gnomad4 ASJ exome AF: 0.423

Gnomad4 EAS exome AF: 0.399

Gnomad4 SAS exome AF: 0.395

Gnomad4 FIN exome AF: 0.591

Gnomad4 NFE exome AF: 0.554

Gnomad4 OTH exome AF: 0.538

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

Gnomad4 AFR AF: 0.854

Gnomad4 AMR AF: 0.619

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.379

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.589

Gnomad4 NFE AF: 0.557

Gnomad4 OTH AF: 0.610

Alfa AF: 0.555 Hom.: 48136

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;T;T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.049	N
MetaRNN	Benign	0.0000020	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.7	N;N;N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.67	T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.13
MutPred		0.41		Loss of catalytic residue at E2610 (P = 0.2439);Loss of catalytic residue at E2610 (P = 0.2439);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs7257948; hg19: chr19-8138054; COSMIC: COSV54462305; COSMIC: COSV54462305;