chr11-10580521-C-T

Variant names:

• chr11-10580521-C-T
• rs185647729
• NM_130385.4:c.2429G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_130385.4(IRAG1):​c.2429G>A​(p.Ser810Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: IRAG1 NM_130385.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0930
• Publications: 1 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]

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

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019432932).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAG1	NM_130385.4	MANE Select	c.2429G>A	p.Ser810Asn	missense	Exon 20 of 21	NP_569056.4
	IRAG1	NM_001098579.3		c.2405G>A	p.Ser802Asn	missense	Exon 19 of 20	NP_001092049.2	Q9Y6F6-9
	IRAG1	NM_001100163.3		c.2156G>A	p.Ser719Asn	missense	Exon 20 of 21	NP_001093633.1	Q9Y6F6-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAG1	ENST00000423302.7	TSL:2 MANE Select	c.2429G>A	p.Ser810Asn	missense	Exon 20 of 21	ENSP00000412130.2	Q9Y6F6-7
	IRAG1	ENST00000534266.6	TSL:2	c.1484G>A	p.Ser495Asn	missense	Exon 18 of 19	ENSP00000433296.2	Q9Y6F6-6
	IRAG1	ENST00000894514.1		c.2531G>A	p.Ser844Asn	missense	Exon 21 of 22	ENSP00000564573.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152182 Hom.: 0 Cov.: 32

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: 0.000514

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000233 AC: 58 AN: 249044 AF XY: 0.000281

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000496

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000328 AC: 480 AN: 1461666 Hom.: 0 Cov.: 32 AF XY: 0.000304 AC XY: 221 AN XY: 727120

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000416 AC: 462 AN: 1111832

Other (OTH) AF: 0.000265 AC: 16 AN: 60372

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74480

African (AFR) AF: 0.0000482 AC: 2 AN: 41526

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000514 AC: 35 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000306 Hom.: 0

Bravo AF: 0.000189

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000364 AC: 3

ExAC AF: 0.000265 AC: 32

EpiCase AF: 0.000654

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.3
DANN	Benign	0.96
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.093
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.037
Sift	Benign	0.17	T
Sift4G	Benign	0.27	T
Vest4		0.12
MVP		0.076
MPC		0.071
ClinPred		0.026	T
GERP RS		1.8
gMVP		0.026
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs185647729; hg19: chr11-10602068;