chr19-8066049-C-T

Position:

• chr19-8066049-C-T

Variant summary

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

The NM_032447.5(FBN3):​c.8300G>A​(p.Arg2767Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000629 in 1,613,068 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: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.252

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=0.051007062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN3	NM_032447.5	c.8300G>A	p.Arg2767Gln	missense_variant	64/64	ENST00000600128.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN3	ENST00000600128.6	c.8300G>A	p.Arg2767Gln	missense_variant	64/64	1	NM_032447.5
FBN3	ENST00000270509.6	c.8300G>A	p.Arg2767Gln	missense_variant	63/63	1
FBN3	ENST00000601739.5	c.8300G>A	p.Arg2767Gln	missense_variant	64/64	1
FBN3	ENST00000651877.1	c.8426G>A	p.Arg2809Gln	missense_variant	64/64			P1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000221 AC: 55 AN: 248978 Hom.: 1 AF XY: 0.000185 AC XY: 25 AN XY: 135072

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000447

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000661 AC: 966 AN: 1460836 Hom.: 0 Cov.: 31 AF XY: 0.000622 AC XY: 452 AN XY: 726746

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000762

Gnomad4 NFE exome AF: 0.000788

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25 AN XY: 74362

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000582 Hom.: 0

Bravo AF: 0.000317

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000491

EpiControl AF: 0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 30, 2023

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FBN3 protein function. This variant has not been reported in the literature in individuals affected with FBN3-related conditions. This variant is present in population databases (rs146438852, gnomAD 0.04%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2767 of the FBN3 protein (p.Arg2767Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.031	T;T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.070	N
LIST_S2	Uncertain	0.88	.;.;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.051	T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	.;N;.
REVEL	Benign	0.14
Sift	Benign	0.20	.;T;.
Sift4G	Benign	0.26	T;T;T
Polyphen		0.41	B;B;B
Vest4		0.12
MVP		0.62
MPC		0.31
ClinPred		0.029	T
GERP RS		-0.39
Varity_R		0.029
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs146438852; hg19: chr19-8130933;