rs121912466

Positions:

• chr17-75742591-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The ENST00000200181.8(ITGB4):​c.2792G>A​(p.Gly931Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ITGB4 ENST00000200181.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.92

Genes affected

ITGB4 (HGNC:6158): (integrin subunit beta 4) Integrins are heterodimers comprised of alpha and beta subunits, that are noncovalently associated transmembrane glycoprotein receptors. Different combinations of alpha and beta polypeptides form complexes that vary in their ligand-binding specificities. Integrins mediate cell-matrix or cell-cell adhesion, and transduced signals that regulate gene expression and cell growth. This gene encodes the integrin beta 4 subunit, a receptor for the laminins. This subunit tends to associate with alpha 6 subunit and is likely to play a pivotal role in the biology of invasive carcinoma. Mutations in this gene are associated with epidermolysis bullosa with pyloric atresia. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862
• PP5: Variant 17-75742591-G-A is Pathogenic according to our data. Variant chr17-75742591-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14740.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ITGB4	NM_000213.5	c.2792G>A	p.Gly931Asp	missense_variant	25/40	ENST00000200181.8	NP_000204.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ITGB4	ENST00000200181.8	c.2792G>A	p.Gly931Asp	missense_variant	25/40	1	NM_000213.5	ENSP00000200181

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Epidermolysis bullosa, junctional 5A, intermediate Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	31
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.56	.;D;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Benign	1.8	L;L;L;L
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.2	.;D;.;D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	.;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.94
MutPred		0.60		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.94
MPC		1.1
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.72
gMVP		0.83

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: rs121912466; hg19: chr17-73738672;