19-8123928-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032447.5(FBN3):c.2812G>A(p.Val938Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 1,614,010 control chromosomes in the GnomAD database, including 3,315 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V938F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.049 (398 hom., cov: 32)
  • Exomes 𝑓: 0.047 (2917 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.233

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022578835).
• BP6: Variant 19-8123928-C-T is Benign according to our data. Variant chr19-8123928-C-T is described in ClinVar as [Benign]. Clinvar id is 1631056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN3	NM_032447.5	c.2812G>A	p.Val938Ile	missense_variant	23/64	ENST00000600128.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN3	ENST00000600128.6	c.2812G>A	p.Val938Ile	missense_variant	23/64	1	NM_032447.5
FBN3	ENST00000270509.6	c.2812G>A	p.Val938Ile	missense_variant	22/63	1
FBN3	ENST00000601739.5	c.2812G>A	p.Val938Ile	missense_variant	23/64	1
FBN3	ENST00000651877.1	c.2938G>A	p.Val980Ile	missense_variant	23/64			P1

Frequencies

GnomAD3 genomes AF: 0.0494 AC: 7513 AN: 152152 Hom.: 395 Cov.: 32

Gnomad AFR AF: 0.0153

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.138

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.0419

Gnomad FIN AF: 0.0816

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.0659

GnomAD3 exomes AF: 0.0722 AC: 18121 AN: 250900 Hom.: 1248 AF XY: 0.0677 AC XY: 9181 AN XY: 135710

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.0280

Gnomad EAS exome AF: 0.205

Gnomad SAS exome AF: 0.0448

Gnomad FIN exome AF: 0.0781

Gnomad NFE exome AF: 0.0339

Gnomad OTH exome AF: 0.0679

GnomAD4 exome AF: 0.0470 AC: 68766 AN: 1461742 Hom.: 2917 Cov.: 32 AF XY: 0.0467 AC XY: 33988 AN XY: 727176

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.190

Gnomad4 ASJ exome AF: 0.0262

Gnomad4 EAS exome AF: 0.213

Gnomad4 SAS exome AF: 0.0483

Gnomad4 FIN exome AF: 0.0735

Gnomad4 NFE exome AF: 0.0352

Gnomad4 OTH exome AF: 0.0525

GnomAD4 genome AF: 0.0494 AC: 7519 AN: 152268 Hom.: 398 Cov.: 32 AF XY: 0.0529 AC XY: 3936 AN XY: 74448

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.139

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.199

Gnomad4 SAS AF: 0.0413

Gnomad4 FIN AF: 0.0816

Gnomad4 NFE AF: 0.0352

Gnomad4 OTH AF: 0.0643

Alfa AF: 0.0431 Hom.: 377

Bravo AF: 0.0550

TwinsUK AF: 0.0388 AC: 144

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.0378 AC: 325

ExAC AF: 0.0644 AC: 7814

Asia WGS AF: 0.112 AC: 388 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

FBN3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

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). -

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	0.082
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.061	N
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.70	N;N;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.43	T
Sift4G	Benign	0.64	T;T;T
Polyphen		0.65	P;P;P
Vest4		0.12
MPC		0.16
ClinPred		0.013	T
GERP RS		-0.095
Varity_R		0.049
gMVP		0.33

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: rs35840170; hg19: chr19-8188812; COSMIC: COSV54457929;