17-75721498-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000213.5(ITGB4):c.-125G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00593 in 121,510 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0059 (6 hom., cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ITGB4 NM_000213.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.833

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 17-75721498-G-C is Benign according to our data. Variant chr17-75721498-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 325118.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00593 (721/121510) while in subpopulation NFE AF= 0.00779 (471/60472). AF 95% confidence interval is 0.00721. There are 6 homozygotes in gnomad4. There are 306 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB4	NM_000213.5	c.-125G>C		5_prime_UTR_variant	1/40	ENST00000200181.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB4	ENST00000200181.8	c.-125G>C		5_prime_UTR_variant	1/40	1	NM_000213.5

Frequencies

GnomAD3 genomes AF: 0.00594 AC: 722 AN: 121478 Hom.: 6 Cov.: 29

Gnomad AFR AF: 0.00284

Gnomad AMI AF: 0.00491

Gnomad AMR AF: 0.00649

Gnomad ASJ AF: 0.0116

Gnomad EAS AF: 0.000557

Gnomad SAS AF: 0.00242

Gnomad FIN AF: 0.00247

Gnomad MID AF: 0.0352

Gnomad NFE AF: 0.00779

Gnomad OTH AF: 0.0107

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 32 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 28

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.00593 AC: 721 AN: 121510 Hom.: 6 Cov.: 29 AF XY: 0.00534 AC XY: 306 AN XY: 57282

Gnomad4 AFR AF: 0.00284

Gnomad4 AMR AF: 0.00647

Gnomad4 ASJ AF: 0.0116

Gnomad4 EAS AF: 0.000560

Gnomad4 SAS AF: 0.00242

Gnomad4 FIN AF: 0.00247

Gnomad4 NFE AF: 0.00779

Gnomad4 OTH AF: 0.0107

Alfa AF: 0.00256 Hom.: 0

Bravo AF: 0.00483

Asia WGS AF: 0.00202 AC: 7 AN: 3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Junctional epidermolysis bullosa with pyloric atresia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

ITGB4: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	7.6
Dann	Benign	0.78

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs552008042; hg19: chr17-73717578;