chr2-181537140-G-A

Variant names:

• chr2-181537140-G-A
• rs16867441
• NM_000885.6:c.*1613G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000885.6(ITGA4):​c.*1613G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00653 in 453,524 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.015 (51 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (20 hom.)
• Consequence: ITGA4 NM_000885.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.881
• Publications: 0 publications found

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]

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 Gene-Disease associations (from GenCC):

• CERKL-related retinopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 26

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.*1613G>A		3_prime_UTR_variant	Exon 28 of 28	ENST00000397033.7	NP_000876.3
CERKL	NM_201548.5	c.*1044C>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000410087.8	NP_963842.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITGA4	ENST00000397033.7	c.*1613G>A		3_prime_UTR_variant	Exon 28 of 28	1	NM_000885.6	ENSP00000380227.2
CERKL	ENST00000410087.8	c.*1044C>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_201548.5	ENSP00000386725.3
CERKL	ENST00000684145.1	c.*1044C>T		3_prime_UTR_variant	Exon 12 of 12			ENSP00000508396.1

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2326 AN: 151942 Hom.: 51 Cov.: 33

Gnomad AFR AF: 0.0531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00453

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0130

GnomAD2 exomes AF: 0.00348 AC: 445 AN: 127744 AF XY: 0.00290

Gnomad AFR exome AF: 0.0587

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.000124

Gnomad EAS exome AF: 0.000288

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000445

Gnomad OTH exome AF: 0.00201

GnomAD4 exome AF: 0.00210 AC: 632 AN: 301464 Hom.: 20 Cov.: 0 AF XY: 0.00167 AC XY: 287 AN XY: 171820

African (AFR) AF: 0.0547 AC: 465 AN: 8500

American (AMR) AF: 0.00213 AC: 58 AN: 27198

Ashkenazi Jewish (ASJ) AF: 0.0000929 AC: 1 AN: 10764

East Asian (EAS) AF: 0.000217 AC: 2 AN: 9208

South Asian (SAS) AF: 0.000252 AC: 15 AN: 59600

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12354

Middle Eastern (MID) AF: 0.00523 AC: 6 AN: 1148

European-Non Finnish (NFE) AF: 0.000290 AC: 46 AN: 158662

Other (OTH) AF: 0.00278 AC: 39 AN: 14030

GnomAD4 genome AF: 0.0153 AC: 2328 AN: 152060 Hom.: 51 Cov.: 33 AF XY: 0.0146 AC XY: 1085 AN XY: 74324

African (AFR) AF: 0.0530 AC: 2200 AN: 41502

American (AMR) AF: 0.00453 AC: 69 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 67940

Other (OTH) AF: 0.0128 AC: 27 AN: 2106

Alfa AF: 0.00752 Hom.: 6

Bravo AF: 0.0177

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, 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	-0.94
CADD	Benign	0.11
DANN	Benign	0.67
PhyloP100		-0.88
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs16867441; hg19: chr2-182401867; COSMIC: COSV59214749; COSMIC: COSV59214749;