rs984330083

Variant names:

• chr2-181536813-G-A
• rs984330083
• NM_000885.6:c.*1286G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000885.6(ITGA4):​c.*1286G>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 0.0000509 in 314,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: ITGA4 NM_000885.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.61
• 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: G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS2: High AC in GnomAd4 at 8 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000885.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA4	NM_000885.6	MANE Select	c.*1286G>A		3_prime_UTR	Exon 28 of 28	NP_000876.3	P13612-1
	CERKL	NM_201548.5	MANE Select	c.*1371C>T		3_prime_UTR	Exon 13 of 13	NP_963842.1	Q49MI3-2
	CERKL	NM_001030311.3		c.*1371C>T		3_prime_UTR	Exon 14 of 14	NP_001025482.1	Q49MI3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITGA4	ENST00000397033.7	TSL:1 MANE Select	c.*1286G>A		3_prime_UTR	Exon 28 of 28	ENSP00000380227.2	P13612-1
	CERKL	ENST00000410087.8	TSL:1 MANE Select	c.*1371C>T		3_prime_UTR	Exon 13 of 13	ENSP00000386725.3	Q49MI3-2
	CERKL	ENST00000684145.1		c.*1371C>T		3_prime_UTR	Exon 12 of 12	ENSP00000508396.1	G0XYE7

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152000 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000668 AC: 4 AN: 59888 AF XY: 0.0000600

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 8 AN: 162298 Hom.: 0 Cov.: 0 AF XY: 0.0000551 AC XY: 5 AN XY: 90672

African (AFR) AF: 0.00 AC: 0 AN: 4236

American (AMR) AF: 0.00 AC: 0 AN: 9152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5054

East Asian (EAS) AF: 0.00 AC: 0 AN: 6522

South Asian (SAS) AF: 0.0000321 AC: 1 AN: 31200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 630

European-Non Finnish (NFE) AF: 0.0000780 AC: 7 AN: 89794

Other (OTH) AF: 0.00 AC: 0 AN: 7788

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152000 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74242

African (AFR) AF: 0.0000483 AC: 2 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15240

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000109 Hom.: 0

Bravo AF: 0.0000680

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.050
DANN	Benign	0.54
PhyloP100		-1.6

Splicing

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

Other links and lift over

dbSNP: rs984330083; hg19: chr2-182401540;