chr17-75752221-C-T

Position:

chr17-75752221-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000213.5(ITGB4):c.3841C>T(p.Arg1281Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1281P) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ITGB4
NM_000213.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.28

Variant links:

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]

ITGB4 links:

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]

GALK1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-75752222-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 3256594.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.876

PP5

Variant 17-75752221-C-T is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB4	NM_000213.5 linkuse as main transcript	c.3841C>T	p.Arg1281Trp	missense_variant	31/40	ENST00000200181.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB4	ENST00000200181.8 linkuse as main transcript	c.3841C>T	p.Arg1281Trp	missense_variant	31/40	1	NM_000213.5		P16144-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251360

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461562

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000633

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 08, 2019

The R1281W variant has been published previously in the homozygous state and with another ITGB4 variant in patiens with JEB-PA (Pulkkinen et al., 1998; Kambham et al., 2000) . It was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project. R1281W is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position within the second fibronectin type III domain that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at the same residue (R1281P) has been reported in the Human Gene Mutation Database in association with epidermolysis bullosa with pyloric atresia (Stenson et al., 2014), supporting the functional importance of this region of the protein. Functional studies of the R1281W variant have shown that it abrogates interaction with plectin, resulting in lack of recruitment at the plasma membrane and abolished tumor-suppressive function (Koster et al., 2001; Raymond et al., 2007). Therefore, we consider the R1281W variant to be pathogenic. -

Junctional epidermolysis bullosa with pyloric atresia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2001

- -

Junctional epidermolysis bullosa

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 26, 2024

Variant summary: ITGB4 c.3841C>T (p.Arg1281Trp) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251360 control chromosomes. c.3841C>T has been reported in the literature in individuals affected with Junctional Epidermolysis Bullosa (example: Pulkkinen_1998). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence showing that this variant prevents the recruitment of plectin into hemidesmosomes in COS-7 cells and abolishes the interaction with plectin in yeast (Koster_2001). The following publications have been ascertained in the context of this evaluation (PMID: 11886501, 9792864). ClinVar contains an entry for this variant (Variation ID: 14742). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

.;T;.;.

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

.;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.88

D;D;D;D

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.7

M;M;M;M

MutationTaster

Benign

1.0

A;A;A;A;A;A

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.9

.;D;.;D

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

.;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;.;D

Vest4

0.98

MutPred

0.65

Gain of ubiquitination at K1279 (P = 0.0599);Gain of ubiquitination at K1279 (P = 0.0599);Gain of ubiquitination at K1279 (P = 0.0599);Gain of ubiquitination at K1279 (P = 0.0599);

MVP

0.90

MPC

1.9

ClinPred

1.0

GERP RS

4.1

Varity_R

0.88

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over