rs878854474

Positions:

• chr5-128361738-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The ENST00000262464.9(FBN2):​c.2539A>G​(p.Thr847Ala) 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. 12/21 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)
• Consequence: FBN2 ENST00000262464.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.544

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 2 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=0.39225894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBN2	NM_001999.4	c.2539A>G	p.Thr847Ala	missense_variant	19/65	ENST00000262464.9	NP_001990.2
FBN2	XM_017009228.3	c.2386A>G	p.Thr796Ala	missense_variant	18/64		XP_016864717.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBN2	ENST00000262464.9	c.2539A>G	p.Thr847Ala	missense_variant	19/65	1	NM_001999.4	ENSP00000262464	P1
FBN2	ENST00000508989.5	c.2440A>G	p.Thr814Ala	missense_variant	18/33	2		ENSP00000425596

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2018

The p.T847A variant (also known as c.2539A>G), located in coding exon 19 of the FBN2 gene, results from an A to G substitution at nucleotide position 2539. The threonine at codon 847 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Congenital contractural arachnodactyly Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2016

In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. This sequence change replaces threonine with alanine at codon 847 of the FBN2 protein (p.Thr847Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.51	D;.;D;D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.90	D;.;.;D
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.35	N;.;N;.
MutationTaster	Benign	0.97	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N;.;N;D
REVEL	Uncertain	0.34
Sift	Benign	0.13	T;.;T;T
Sift4G	Benign	0.80	.;.;.;T
Polyphen		0.35	B;.;B;P
Vest4		0.45
MutPred		0.56		Loss of phosphorylation at T847 (P = 0.0644);.;Loss of phosphorylation at T847 (P = 0.0644);.;
MVP		0.64
MPC		0.55
ClinPred		0.79	D
GERP RS		3.6
Varity_R		0.15
gMVP		0.54

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: rs878854474; hg19: chr5-127697431;