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 in gene, where missense usually causes diseases (based on misZ statistic), FBN2. . Gene score misZ 1.5491 (greater than the threshold 3.09). Trascript score misZ 3.2752 (greater than threshold 3.09). GenCC has associacion of gene with familial thoracic aortic aneurysm and aortic dissection, carpal tunnel syndrome, macular degeneration, early-onset, congenital contractural arachnodactyly.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25609082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.4627G>A	p.Val1543Ile	missense_variant	36/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.4474G>A	p.Val1492Ile	missense_variant	35/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.4627G>A	p.Val1543Ile	missense_variant	36/65	1	NM_001999.4	ENSP00000262464	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

Labcorp Genetics (formerly Invitae), Labcorp

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;