11-10647681-T-C

Variant names:

• chr11-10647681-T-C
• rs7940646
• NM_130385.4:c.225+4344A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_130385.4(IRAG1):​c.225+4344A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 152,122 control chromosomes in the GnomAD database, including 47,527 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.78 (47527 hom., cov: 31)
• Consequence: IRAG1 NM_130385.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0140
• Publications: 27 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.959 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAG1	NM_130385.4	MANE Select	c.225+4344A>G		intron	N/A	NP_569056.4
	IRAG1	NM_001098579.3		c.198+4344A>G		intron	N/A	NP_001092049.2
	IRAG1	NM_001100163.3		c.-48-13610A>G		intron	N/A	NP_001093633.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAG1	ENST00000423302.7	TSL:2 MANE Select	c.225+4344A>G		intron	N/A	ENSP00000412130.2
	IRAG1	ENST00000534266.6	TSL:2	c.-671+4344A>G		intron	N/A	ENSP00000433296.2
	IRAG1	ENST00000526414.5	TSL:2	n.69+4344A>G		intron	N/A	ENSP00000435658.1

Frequencies

GnomAD3 genomes AF: 0.780 AC: 118588 AN: 152004 Hom.: 47475 Cov.: 31

Gnomad AFR AF: 0.944

Gnomad AMI AF: 0.511

Gnomad AMR AF: 0.786

Gnomad ASJ AF: 0.711

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.849

Gnomad FIN AF: 0.671

Gnomad MID AF: 0.655

Gnomad NFE AF: 0.684

Gnomad OTH AF: 0.775

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.780 AC: 118700 AN: 152122 Hom.: 47527 Cov.: 31 AF XY: 0.781 AC XY: 58103 AN XY: 74354

African (AFR) AF: 0.944 AC: 39199 AN: 41520

American (AMR) AF: 0.786 AC: 11998 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.711 AC: 2468 AN: 3470

East Asian (EAS) AF: 0.981 AC: 5061 AN: 5158

South Asian (SAS) AF: 0.847 AC: 4086 AN: 4822

European-Finnish (FIN) AF: 0.671 AC: 7096 AN: 10578

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.684 AC: 46501 AN: 67986

Other (OTH) AF: 0.775 AC: 1636 AN: 2112

Alfa AF: 0.716 Hom.: 116871

Bravo AF: 0.795

Asia WGS AF: 0.914 AC: 3175 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.9
DANN	Benign	0.75
PhyloP100		0.014
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7940646; hg19: chr11-10669228;