17-75752241-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000213.5(ITGB4):c.3861C>T(p.Asn1287=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00342 in 1,613,712 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (10 hom.)
• Consequence: ITGB4 NM_000213.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.75

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 17-75752241-C-T is Benign according to our data. Variant chr17-75752241-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 325186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-75752241-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.74 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0023 (351/152364) while in subpopulation NFE AF= 0.00453 (308/68022). AF 95% confidence interval is 0.00411. There are 2 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGB4	NM_000213.5	c.3861C>T	p.Asn1287=	synonymous_variant	31/40	ENST00000200181.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGB4	ENST00000200181.8	c.3861C>T	p.Asn1287=	synonymous_variant	31/40	1	NM_000213.5

Frequencies

GnomAD3 genomes AF: 0.00231 AC: 351 AN: 152246 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00453

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00195 AC: 490 AN: 251278 Hom.: 3 AF XY: 0.00194 AC XY: 264 AN XY: 135872

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00377

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00353 AC: 5165 AN: 1461348 Hom.: 10 Cov.: 33 AF XY: 0.00347 AC XY: 2521 AN XY: 726974

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000850

Gnomad4 NFE exome AF: 0.00442

Gnomad4 OTH exome AF: 0.00237

GnomAD4 genome AF: 0.00230 AC: 351 AN: 152364 Hom.: 2 Cov.: 33 AF XY: 0.00197 AC XY: 147 AN XY: 74504

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00453

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00171 Hom.: 0

Bravo AF: 0.00237

EpiCase AF: 0.00365

EpiControl AF: 0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ITGB4: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Junctional epidermolysis bullosa with pyloric atresia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
Cadd	Benign	6.1
Dann	Benign	0.80

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

Other links and lift over

dbSNP: rs145351926; hg19: chr17-73748322;