chr2-181536860-C-T

Position:

chr2-181536860-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000885.6(ITGA4):c.*1333C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 427,446 control chromosomes in the GnomAD database, including 98 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.017 ( 33 hom., cov: 33)

Exomes 𝑓: 0.018 ( 65 hom. )

Consequence

ITGA4
NM_000885.6 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.433

Variant links:

Genes affected

ITGA4 (HGNC:6140): (integrin subunit alpha 4) The gene encodes a member of the integrin alpha chain family of proteins. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain that function in cell surface adhesion and signaling. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha 4 subunit. This subunit associates with a beta 1 or beta 7 subunit to form an integrin that may play a role in cell motility and migration. This integrin is a therapeutic target for the treatment of multiple sclerosis, Crohn's disease and inflammatory bowel disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2015]

ITGA4 links:

CERKL (HGNC:21699): (ceramide kinase like) This gene was initially identified as a locus (RP26) associated with an autosomal recessive form of retinitis pigmentosa (arRP) disease. This gene encodes a protein with ceramide kinase-like domains, however, the protein does not phosphorylate ceramide and its target substrate is currently unknown. This protein may be a negative regulator of apoptosis in photoreceptor cells. Mutations in this gene cause a form of retinitis pigmentosa characterized by autosomal recessive cone and rod dystrophy (arCRD). Alternative splicing of this gene results in multiple transcript variants encoding different isoforms and non-coding transcripts.[provided by RefSeq, May 2010]

CERKL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0168 (2556/152008) while in subpopulation NFE AF= 0.0276 (1874/67944). AF 95% confidence interval is 0.0265. There are 33 homozygotes in gnomad4. There are 1152 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 2556 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITGA4	NM_000885.6 linkuse as main transcript	c.*1333C>T		3_prime_UTR_variant	28/28	ENST00000397033.7
CERKL	NM_201548.5 linkuse as main transcript	c.*1324G>A		3_prime_UTR_variant	13/13	ENST00000410087.8

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITGA4	ENST00000397033.7 linkuse as main transcript	c.*1333C>T	3_prime_UTR_variant	28/28	1	NM_000885.6	P1	P13612-1
CERKL	ENST00000410087.8 linkuse as main transcript	c.*1324G>A	3_prime_UTR_variant	13/13	1	NM_201548.5	P1	Q49MI3-2
CERKL	ENST00000684145.1 linkuse as main transcript	c.*1324G>A	3_prime_UTR_variant	12/12

Frequencies

GnomAD3 genomes

AF:

0.0168

AC:

2558

AN:

151888

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00484

Gnomad AMI

AF:

0.00877

Gnomad AMR

AF:

0.0181

Gnomad ASJ

AF:

0.00664

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0119

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.0276

Gnomad OTH

AF:

0.0144

GnomAD3 exomes

AF:

0.0153

AC:

1764

AN:

114956

Hom.:

AF XY:

0.0153

AC XY:

965

AN XY:

63072

show subpopulations

Gnomad AFR exome

AF:

0.00402

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.00643

Gnomad EAS exome

AF:

0.000102

Gnomad SAS exome

AF:

0.00177

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.0281

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0183

AC:

5033

AN:

275438

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

2626

AN XY:

156534

show subpopulations

Gnomad4 AFR exome

AF:

0.00548

Gnomad4 AMR exome

AF:

0.0155

Gnomad4 ASJ exome

AF:

0.00728

Gnomad4 EAS exome

AF:

0.000115

Gnomad4 SAS exome

AF:

0.00245

Gnomad4 FIN exome

AF:

0.0133

Gnomad4 NFE exome

AF:

0.0275

Gnomad4 OTH exome

AF:

0.0175

GnomAD4 genome

AF:

0.0168

AC:

2556

AN:

152008

Hom.:

Cov.:

AF XY:

0.0155

AC XY:

1152

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.00482

Gnomad4 AMR

AF:

0.0180

Gnomad4 ASJ

AF:

0.00664

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.0119

Gnomad4 NFE

AF:

0.0276

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.0209

Hom.:

Bravo

AF:

0.0168

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Retinitis pigmentosa

Uncertain:1

Uncertain significance, 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, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

3.3

DANN

Benign

0.48

Splicing

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