2-181537230-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000885.6(ITGA4):c.*1703G>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 0.128 in 452,766 control chromosomes in the GnomAD database, including 4,653 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2037 hom., cov: 33)

Exomes 𝑓: 0.12 ( 2616 hom. )

Consequence

ITGA4
NM_000885.6 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.191

Publications

5 publications found

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 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

CERKL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

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

BP6

Variant 2-181537230-G-T is Benign according to our data. Variant chr2-181537230-G-T is described in ClinVar as Benign. ClinVar VariationId is 332985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ITGA4	NM_000885.6	MANE Select	c.*1703G>T	3_prime_UTR	Exon 28 of 28	NP_000876.3	P13612-1
CERKL	NM_201548.5	MANE Select	c.*954C>A	3_prime_UTR	Exon 13 of 13	NP_963842.1	Q49MI3-2
CERKL	NM_001030311.3		c.*954C>A	3_prime_UTR	Exon 14 of 14	NP_001025482.1	Q49MI3-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ITGA4	ENST00000397033.7	TSL:1 MANE Select	c.*1703G>T	3_prime_UTR	Exon 28 of 28	ENSP00000380227.2	P13612-1
CERKL	ENST00000410087.8	TSL:1 MANE Select	c.*954C>A	3_prime_UTR	Exon 13 of 13	ENSP00000386725.3	Q49MI3-2
CERKL	ENST00000684145.1		c.*954C>A	3_prime_UTR	Exon 12 of 12	ENSP00000508396.1	G0XYE7

Frequencies

GnomAD3 genomes

AF:

0.153

AC:

23145

AN:

151500

Hom.:

2037

Cov.:

show subpopulations

Gnomad AFR

AF:

0.218

Gnomad AMI

AF:

0.0482

Gnomad AMR

AF:

0.179

Gnomad ASJ

AF:

0.0704

Gnomad EAS

AF:

0.219

Gnomad SAS

AF:

0.0595

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.120

GnomAD2 exomes

AF:

0.134

AC:

17091

AN:

127790

AF XY:

0.123

show subpopulations

Gnomad AFR exome

AF:

0.233

Gnomad AMR exome

AF:

0.211

Gnomad ASJ exome

AF:

0.0705

Gnomad EAS exome

AF:

0.214

Gnomad FIN exome

AF:

0.209

Gnomad NFE exome

AF:

0.105

Gnomad OTH exome

AF:

0.123

GnomAD4 exome

AF:

0.116

AC:

34989

AN:

301148

Hom.:

2616

Cov.:

AF XY:

0.108

AC XY:

18508

AN XY:

171668

show subpopulations

African (AFR)

AF:

0.227

AC:

1941

AN:

8536

American (AMR)

AF:

0.211

AC:

5767

AN:

27268

Ashkenazi Jewish (ASJ)

AF:

0.0680

AC:

733

AN:

10784

East Asian (EAS)

AF:

0.219

AC:

2008

AN:

9164

South Asian (SAS)

AF:

0.0512

AC:

3054

AN:

59642

European-Finnish (FIN)

AF:

0.200

AC:

2463

AN:

12308

Middle Eastern (MID)

AF:

0.0548

AC:

AN:

1150

European-Non Finnish (NFE)

AF:

0.109

AC:

17250

AN:

158284

Other (OTH)

AF:

0.122

AC:

1710

AN:

14012

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

2096

4193

6289

8386

10482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

166

332

498

664

830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.153

AC:

23170

AN:

151618

Hom.:

2037

Cov.:

AF XY:

0.157

AC XY:

11601

AN XY:

74120

show subpopulations

African (AFR)

AF:

0.218

AC:

9040

AN:

41380

American (AMR)

AF:

0.178

AC:

2715

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.0704

AC:

244

AN:

3468

East Asian (EAS)

AF:

0.218

AC:

1126

AN:

5160

South Asian (SAS)

AF:

0.0594

AC:

286

AN:

4816

European-Finnish (FIN)

AF:

0.192

AC:

2019

AN:

10536

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.110

AC:

7426

AN:

67726

Other (OTH)

AF:

0.122

AC:

257

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

987

1973

2960

3946

4933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

248

496

744

992

1240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.129

Hom.:

2323

Bravo

AF:

0.155

Asia WGS

AF:

0.172

AC:

598

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.86

(source)

DANN

Benign

0.45

PhyloP100

0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over