2-181537304-C-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.*1777C>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 0.997 in 453,948 control chromosomes in the GnomAD database, including 225,533 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.99 ( 75033 hom., cov: 31)

Exomes 𝑓: 1.0 ( 150500 hom. )

Consequence

ITGA4
NM_000885.6 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.33

Publications

4 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=-1.0).

BP6

Variant 2-181537304-C-T is Benign according to our data. Variant chr2-181537304-C-T is described in ClinVar as Benign. ClinVar VariationId is 332987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.994 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.*1777C>T	3_prime_UTR	Exon 28 of 28	NP_000876.3	P13612-1
CERKL	NM_201548.5	MANE Select	c.*880G>A	3_prime_UTR	Exon 13 of 13	NP_963842.1	Q49MI3-2
CERKL	NM_001030311.3		c.*880G>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.*1777C>T	3_prime_UTR	Exon 28 of 28	ENSP00000380227.2	P13612-1
CERKL	ENST00000410087.8	TSL:1 MANE Select	c.*880G>A	3_prime_UTR	Exon 13 of 13	ENSP00000386725.3	Q49MI3-2
CERKL	ENST00000684145.1		c.*880G>A	3_prime_UTR	Exon 12 of 12	ENSP00000508396.1	G0XYE7

Frequencies

GnomAD3 genomes

AF:

0.993

AC:

151002

AN:

152072

Hom.:

74983

Cov.:

show subpopulations

Gnomad AFR

AF:

0.977

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.996

Gnomad ASJ

AF:

0.996

Gnomad EAS

AF:

0.996

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.994

GnomAD2 exomes

AF:

0.998

AC:

127662

AN:

127950

AF XY:

0.998

show subpopulations

Gnomad AFR exome

AF:

0.979

Gnomad AMR exome

AF:

0.998

Gnomad ASJ exome

AF:

0.995

Gnomad EAS exome

AF:

0.994

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.998

GnomAD4 exome

AF:

0.999

AC:

301376

AN:

301758

Hom.:

150500

Cov.:

AF XY:

0.999

AC XY:

171806

AN XY:

171972

show subpopulations

African (AFR)

AF:

0.981

AC:

8384

AN:

8548

American (AMR)

AF:

0.998

AC:

27231

AN:

27274

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

10738

AN:

10786

East Asian (EAS)

AF:

0.995

AC:

9161

AN:

9208

South Asian (SAS)

AF:

1.00

AC:

59619

AN:

59642

European-Finnish (FIN)

AF:

1.00

AC:

12364

AN:

12364

Middle Eastern (MID)

AF:

0.998

AC:

1148

AN:

1150

European-Non Finnish (NFE)

AF:

1.00

AC:

158718

AN:

158744

Other (OTH)

AF:

0.998

AC:

14013

AN:

14042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

626

1252

1878

2504

3130

<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:

0.993

AC:

151111

AN:

152190

Hom.:

75033

Cov.:

AF XY:

0.993

AC XY:

73889

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.977

AC:

40566

AN:

41520

American (AMR)

AF:

0.996

AC:

15201

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.996

AC:

3455

AN:

3470

East Asian (EAS)

AF:

0.996

AC:

5151

AN:

5174

South Asian (SAS)

AF:

1.00

AC:

4826

AN:

4826

European-Finnish (FIN)

AF:

1.00

AC:

10614

AN:

10614

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

67993

AN:

68002

Other (OTH)

AF:

0.994

AC:

2099

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

102

154

205

256

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.996

Hom.:

13988

Bravo

AF:

0.992

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

-1.0

CADD

Benign

0.16

(source)

DANN

Benign

0.53

PhyloP100

-2.3

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