17-75752222-G-C

Position:

• chr17-75752222-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Moderate PP5_Moderate

The NM_000213.5(ITGB4):​c.3842G>C​(p.Arg1281Pro) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1281W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ITGB4 NM_000213.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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]

GALK1 (HGNC:4118): (galactokinase 1) Galactokinase is a major enzyme for the metabolism of galactose and its deficiency causes congenital cataracts during infancy and presenile cataracts in the adult population. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-75752221-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 14742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 17-75752222-G-C is Pathogenic according to our data. Variant chr17-75752222-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3256594.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB4	NM_000213.5	c.3842G>C	p.Arg1281Pro	missense_variant	31/40	ENST00000200181.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB4	ENST00000200181.8	c.3842G>C	p.Arg1281Pro	missense_variant	31/40	1	NM_000213.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Junctional epidermolysis bullosa with pyloric atresia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Feb 19, 2024

PM2, PM5, PP3, PP4, PP5 - The variant was detected in trans with NM_001005731.3:c.4295_4298dup variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	30
DANN	Benign	0.97
DEOGEN2	Benign	0.37	.;T;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.2	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	.;D;.;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	.;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.98
MutPred		0.71		Gain of glycosylation at R1281 (P = 0.0342);Gain of glycosylation at R1281 (P = 0.0342);Gain of glycosylation at R1281 (P = 0.0342);Gain of glycosylation at R1281 (P = 0.0342);
MVP		0.89
MPC		2.2
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.95
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-73748303;