17-75752221-C-T

Variant names:

• chr17-75752221-C-T
• rs121912467
• NM_000213.5:c.3841C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.28
• Publications: 16 publications found

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]

GALK1 Gene-Disease associations (from GenCC):

• galactokinase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 14742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000213.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB4	NM_000213.5	MANE Select	c.3841C>T	p.Arg1281Trp	missense	Exon 31 of 40	NP_000204.3
	ITGB4	NM_001005619.2		c.3841C>T	p.Arg1281Trp	missense	Exon 31 of 40	NP_001005619.1
	ITGB4	NM_001005731.3		c.3841C>T	p.Arg1281Trp	missense	Exon 31 of 39	NP_001005731.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGB4	ENST00000200181.8	TSL:1 MANE Select	c.3841C>T	p.Arg1281Trp	missense	Exon 31 of 40	ENSP00000200181.3
	ITGB4	ENST00000449880.7	TSL:1	c.3841C>T	p.Arg1281Trp	missense	Exon 31 of 40	ENSP00000400217.2
	ITGB4	ENST00000450894.7	TSL:1	c.3841C>T	p.Arg1281Trp	missense	Exon 31 of 39	ENSP00000405536.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251360 AF XY: 0.00000736

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461562 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727086

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000382 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Junctional epidermolysis bullosa with pyloric atresia;C5676956:Epidermolysis bullosa, junctional 5A, intermediate Pathogenic:1

May 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Pathogenic:1

Jan 08, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Junctional epidermolysis bullosa Pathogenic:1

Apr 26, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.65		Gain of ubiquitination at K1279 (P = 0.0599)
MVP		0.90
MPC		1.9
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.88
gMVP		0.85
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121912467; hg19: chr17-73748302;