chr19-8066124-A-T

Variant names:

• chr19-8066124-A-T
• rs747732485
• NM_032447.5:c.8225T>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032447.5(FBN3):​c.8225T>A​(p.Val2742Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.992

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05944234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBN3	NM_032447.5	c.8225T>A	p.Val2742Asp	missense_variant	Exon 64 of 64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.8225T>A	p.Val2742Asp	missense_variant	Exon 64 of 64	1	NM_032447.5	ENSP00000470498.1
FBN3	ENST00000270509.6	c.8225T>A	p.Val2742Asp	missense_variant	Exon 63 of 63	1		ENSP00000270509.2
FBN3	ENST00000601739.5	c.8225T>A	p.Val2742Asp	missense_variant	Exon 64 of 64	1		ENSP00000472324.1
FBN3	ENST00000651877.1	c.8351T>A	p.Val2784Asp	missense_variant	Exon 64 of 64			ENSP00000498507.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249352 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461210 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2742 of the FBN3 protein (p.Val2742Asp). This variant is present in population databases (rs747732485, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with FBN3-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FBN3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	8.7
DANN	Benign	0.55
DEOGEN2	Benign	0.025	T;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.58	.;.;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.76	.;N;.
REVEL	Benign	0.19
Sift	Benign	0.57	.;T;.
Sift4G	Benign	0.41	T;T;T
Polyphen		0.026	B;B;B
Vest4		0.075
MutPred		0.54		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		0.45
MPC		0.32
ClinPred		0.026	T
GERP RS		1.1
Varity_R		0.092
gMVP		0.70

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: rs747732485; hg19: chr19-8131008;