rs1554121038

Positions:

• chr5-128318239-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001999.4(FBN2):​c.4627G>A​(p.Val1543Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.42

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FBN2
• BP4: Computational evidence support a benign effect (MetaRNN=0.25609082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.4627G>A	p.Val1543Ile	missense_variant	36/65	ENST00000262464.9
FBN2	XM_017009228.3	c.4474G>A	p.Val1492Ile	missense_variant	35/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.4627G>A	p.Val1543Ile	missense_variant	36/65	1	NM_001999.4	P1
FBN2	ENST00000703783.1	n.1411G>A		non_coding_transcript_exon_variant	11/38
FBN2	ENST00000703785.1	n.1492G>A		non_coding_transcript_exon_variant	11/27

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital contractural arachnodactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 26, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a FBN2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). This sequence change replaces valine with isoleucine at codon 1543 of the FBN2 protein (p.Val1543Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.28
DEOGEN2	Benign	0.21	T;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.62	T;.;.
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.56	N;.;N
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.36	N;.;N
REVEL	Uncertain	0.48
Sift	Benign	1.0	T;.;T
Polyphen		0.0020	B;.;B
Vest4		0.21
MutPred		0.52		Loss of catalytic residue at V1543 (P = 0.0866);.;Loss of catalytic residue at V1543 (P = 0.0866);
MVP		0.30
MPC		0.21
ClinPred		0.65	D
GERP RS		5.2
Varity_R		0.076
gMVP		0.70

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: rs1554121038; hg19: chr5-127653931;