chr2-181537025-G-A

Variant names:

• chr2-181537025-G-A
• rs1047307
• NM_000885.6:c.*1498G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000885.6(ITGA4):​c.*1498G>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 0.38 in 444,670 control chromosomes in the GnomAD database, including 35,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8696 hom., cov: 33)
  • Exomes 𝑓: 0.41 (26485 hom.)
• Consequence: ITGA4 NM_000885.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.567
• Publications: 12 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-181537025-G-A is Benign according to our data. Variant chr2-181537025-G-A is described in ClinVar as [Benign]. Clinvar id is 332981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITGA4	NM_000885.6	c.*1498G>A		3_prime_UTR_variant	Exon 28 of 28	ENST00000397033.7	NP_000876.3
CERKL	NM_201548.5	c.*1159C>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.*1498G>A		3_prime_UTR_variant	Exon 28 of 28	1	NM_000885.6	ENSP00000380227.2
CERKL	ENST00000410087.8	c.*1159C>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_201548.5	ENSP00000386725.3
CERKL	ENST00000684145.1	c.*1159C>T		3_prime_UTR_variant	Exon 12 of 12			ENSP00000508396.1

Frequencies

GnomAD3 genomes AF: 0.327 AC: 49668 AN: 151888 Hom.: 8697 Cov.: 33

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.248

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.488

Gnomad SAS AF: 0.632

Gnomad FIN AF: 0.292

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.359

GnomAD2 exomes AF: 0.409 AC: 49715 AN: 121576 AF XY: 0.424

Gnomad AFR exome AF: 0.231

Gnomad AMR exome AF: 0.356

Gnomad ASJ exome AF: 0.411

Gnomad EAS exome AF: 0.486

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.389

GnomAD4 exome AF: 0.408 AC: 119269 AN: 292664 Hom.: 26485 Cov.: 0 AF XY: 0.431 AC XY: 71752 AN XY: 166460

African (AFR) AF: 0.227 AC: 1858 AN: 8190

American (AMR) AF: 0.354 AC: 9305 AN: 26260

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 4289 AN: 10238

East Asian (EAS) AF: 0.483 AC: 4404 AN: 9118

South Asian (SAS) AF: 0.623 AC: 36186 AN: 58126

European-Finnish (FIN) AF: 0.270 AC: 3236 AN: 11966

Middle Eastern (MID) AF: 0.462 AC: 504 AN: 1090

European-Non Finnish (NFE) AF: 0.353 AC: 54427 AN: 154054

Other (OTH) AF: 0.371 AC: 5060 AN: 13622

GnomAD4 genome AF: 0.327 AC: 49689 AN: 152006 Hom.: 8696 Cov.: 33 AF XY: 0.331 AC XY: 24622 AN XY: 74290

African (AFR) AF: 0.227 AC: 9433 AN: 41490

American (AMR) AF: 0.345 AC: 5254 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1444 AN: 3470

East Asian (EAS) AF: 0.489 AC: 2529 AN: 5172

South Asian (SAS) AF: 0.632 AC: 3047 AN: 4822

European-Finnish (FIN) AF: 0.292 AC: 3087 AN: 10568

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23799 AN: 67932

Other (OTH) AF: 0.356 AC: 749 AN: 2102

Alfa AF: 0.339 Hom.: 19807

Bravo AF: 0.320

Asia WGS AF: 0.516 AC: 1795 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Retinitis pigmentosa Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.8
DANN	Benign	0.66
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1047307; hg19: chr2-182401752;