17-75754778-C-G

Variant names:

• chr17-75754778-C-G
• rs8669
• NM_000213.5:c.4521C>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000213.5(ITGB4):​c.4521C>G​(p.Pro1507Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 1,613,648 control chromosomes in the GnomAD database, including 182,550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1507P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.39 (13132 hom., cov: 32)
  • Exomes 𝑓: 0.48 (169418 hom.)
• Consequence: ITGB4 NM_000213.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.19
• Publications: 25 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 17-75754778-C-G is Benign according to our data. Variant chr17-75754778-C-G is described in ClinVar as Benign. ClinVar VariationId is 255542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

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.4521C>G	p.Pro1507Pro	synonymous	Exon 34 of 40	NP_000204.3
	ITGB4	NM_001005619.2		c.4311C>G	p.Pro1437Pro	synonymous	Exon 33 of 40	NP_001005619.1
	ITGB4	NM_001005731.3		c.4311C>G	p.Pro1437Pro	synonymous	Exon 33 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.4521C>G	p.Pro1507Pro	synonymous	Exon 34 of 40	ENSP00000200181.3
	ITGB4	ENST00000449880.7	TSL:1	c.4311C>G	p.Pro1437Pro	synonymous	Exon 33 of 40	ENSP00000400217.2
	ITGB4	ENST00000450894.7	TSL:1	c.4311C>G	p.Pro1437Pro	synonymous	Exon 33 of 39	ENSP00000405536.3

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58544 AN: 151918 Hom.: 13135 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.369

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.484

Gnomad MID AF: 0.367

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.415

GnomAD2 exomes AF: 0.455 AC: 114338 AN: 251118 AF XY: 0.460

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.471

Gnomad ASJ exome AF: 0.385

Gnomad EAS exome AF: 0.512

Gnomad FIN exome AF: 0.481

Gnomad NFE exome AF: 0.493

Gnomad OTH exome AF: 0.454

GnomAD4 exome AF: 0.477 AC: 696779 AN: 1461612 Hom.: 169418 Cov.: 55 AF XY: 0.476 AC XY: 346136 AN XY: 727118

African (AFR) AF: 0.126 AC: 4223 AN: 33476

American (AMR) AF: 0.466 AC: 20842 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.383 AC: 10009 AN: 26136

East Asian (EAS) AF: 0.460 AC: 18265 AN: 39696

South Asian (SAS) AF: 0.443 AC: 38192 AN: 86250

European-Finnish (FIN) AF: 0.485 AC: 25888 AN: 53382

Middle Eastern (MID) AF: 0.402 AC: 2317 AN: 5766

European-Non Finnish (NFE) AF: 0.494 AC: 549779 AN: 1111808

Other (OTH) AF: 0.451 AC: 27264 AN: 60388

GnomAD4 genome AF: 0.385 AC: 58538 AN: 152036 Hom.: 13132 Cov.: 32 AF XY: 0.389 AC XY: 28927 AN XY: 74302

African (AFR) AF: 0.138 AC: 5714 AN: 41500

American (AMR) AF: 0.468 AC: 7149 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 1282 AN: 3472

East Asian (EAS) AF: 0.494 AC: 2542 AN: 5150

South Asian (SAS) AF: 0.447 AC: 2154 AN: 4820

European-Finnish (FIN) AF: 0.484 AC: 5117 AN: 10582

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.489 AC: 33203 AN: 67908

Other (OTH) AF: 0.419 AC: 884 AN: 2112

Alfa AF: 0.419 Hom.: 4233

Bravo AF: 0.372

Asia WGS AF: 0.449 AC: 1563 AN: 3478

EpiCase AF: 0.479

EpiControl AF: 0.488

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Junctional epidermolysis bullosa with pyloric atresia Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Junctional epidermolysis bullosa, non-Herlitz type Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Epidermolysis bullosa simplex 1C, localized Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Deficiency of galactokinase Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.1
DANN	Benign	0.84
PhyloP100		1.2
PromoterAI		-0.014	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8669; hg19: chr17-73750859; COSMIC: COSV52325966; COSMIC: COSV52325966;