rs35840170

Positions:

• chr19-8123928-C-A
• chr19-8123928-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032447.5(FBN3):​c.2812G>T​(p.Val938Phe) 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 1,461,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FBN3 NM_032447.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37187514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN3	NM_032447.5	c.2812G>T	p.Val938Phe	missense_variant	23/64	ENST00000600128.6	NP_115823.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN3	ENST00000600128.6	c.2812G>T	p.Val938Phe	missense_variant	23/64	1	NM_032447.5	ENSP00000470498.1
FBN3	ENST00000270509.6	c.2812G>T	p.Val938Phe	missense_variant	22/63	1		ENSP00000270509.2
FBN3	ENST00000601739.5	c.2812G>T	p.Val938Phe	missense_variant	23/64	1		ENSP00000472324.1
FBN3	ENST00000651877.1	c.2938G>T	p.Val980Phe	missense_variant	23/64			ENSP00000498507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461768 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727188

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.3	M;M;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.3	.;N;.
REVEL	Uncertain	0.34
Sift	Benign	0.036	.;D;.
Sift4G	Benign	0.47	T;T;T
Polyphen		0.93	P;P;P
Vest4		0.40
MutPred		0.22		Loss of ubiquitination at K933 (P = 0.1287);Loss of ubiquitination at K933 (P = 0.1287);Loss of ubiquitination at K933 (P = 0.1287);
MVP		0.64
MPC		0.68
ClinPred		0.93	D
GERP RS		-0.095
Varity_R		0.19
gMVP		0.65

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;