11-10603124-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_130385.4(IRAG1):c.1871G>A(p.Arg624His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,608,482 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R624C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

IRAG1
NM_130385.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.33

Publications

1 publications found

Variant links:

Genes affected

IRAG1 (HGNC:7237): (inositol 1,4,5-triphosphate receptor associated 1) This gene is similar to a putative mouse tumor suppressor gene (Mrvi1) that is frequently disrupted by mouse AIDS-related virus (MRV). The encoded protein, which is found in the membrane of the endoplasmic reticulum, is similar to Jaw1, a lymphoid-restricted protein whose expression is down-regulated during lymphoid differentiation. This protein is a substrate of cGMP-dependent kinase-1 (PKG1) that can function as a regulator of IP3-induced calcium release. Studies in mouse suggest that MRV integration at Mrvi1 induces myeloid leukemia by altering the expression of a gene important for myeloid cell growth and/or differentiation, and thus this gene may function as a myeloid leukemia tumor suppressor gene. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene, and alternative translation start sites, including a non-AUG (CUG) start site, are used. [provided by RefSeq, May 2011]

IRAG1 links:

LYVE1 (HGNC:14687): (lymphatic vessel endothelial hyaluronan receptor 1) This gene encodes a type I integral membrane glycoprotein. The encoded protein acts as a receptor and binds to both soluble and immobilized hyaluronan. This protein may function in lymphatic hyaluronan transport and have a role in tumor metastasis. [provided by RefSeq, Jul 2008]

LYVE1 links:

IRAG1-AS1 (HGNC:43434): (IRAG1 antisense RNA 1)

IRAG1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3885246).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130385.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRAG1	NM_130385.4	MANE Select	c.1871G>A	p.Arg624His	missense	Exon 14 of 21	NP_569056.4
IRAG1	NM_001098579.3		c.1847G>A	p.Arg616His	missense	Exon 13 of 20	NP_001092049.2	Q9Y6F6-9
IRAG1	NM_001100163.3		c.1598G>A	p.Arg533His	missense	Exon 14 of 21	NP_001093633.1	Q9Y6F6-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRAG1	ENST00000423302.7	TSL:2 MANE Select	c.1871G>A	p.Arg624His	missense	Exon 14 of 21	ENSP00000412130.2	Q9Y6F6-7
IRAG1	ENST00000534266.6	TSL:2	c.926G>A	p.Arg309His	missense	Exon 12 of 19	ENSP00000433296.2	Q9Y6F6-6
IRAG1	ENST00000526414.5	TSL:2	n.1100G>A		non_coding_transcript_exon	Exon 13 of 17	ENSP00000435658.1	E9PJ61

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000502

AC:

AN:

238896

AF XY:

0.0000385

show subpopulations

Gnomad AFR exome

AF:

0.0000691

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000502

Gnomad NFE exome

AF:

0.0000463

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1456446

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

724138

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33414

American (AMR)

AF:

0.0000906

AC:

AN:

44136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26012

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39546

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5668

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1109920

Other (OTH)

AF:

0.0000332

AC:

AN:

60216

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000460

AC:

AN:

152036

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41390

American (AMR)

AF:

0.0000655

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000431

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000579

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.078

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.077

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.043

MetaRNN

Benign

0.39

MetaSVM

Benign

-1.1

PhyloP100

7.3

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.86

REVEL

Benign

0.23

Sift

Benign

0.13

Sift4G

Uncertain

0.023

Vest4

0.85

MVP

0.39

MPC

0.48

ClinPred

0.63

GERP RS

5.4

gMVP

0.40

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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