NM_130385.4:c.2624A>T

Variant names:

• chr11-10576447-T-A
• rs748752897
• NM_130385.4:c.2624A>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_130385.4(IRAG1):​c.2624A>T​(p.Tyr875Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRAG1 NM_130385.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.065062344).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAG1	NM_130385.4	c.2624A>T	p.Tyr875Phe	missense_variant	Exon 21 of 21	ENST00000423302.7	NP_569056.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAG1	ENST00000423302.7	c.2624A>T	p.Tyr875Phe	missense_variant	Exon 21 of 21	2	NM_130385.4	ENSP00000412130.2
IRAG1	ENST00000534266.6	c.1679A>T	p.Tyr560Phe	missense_variant	Exon 19 of 19	2		ENSP00000433296.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2624A>T (p.Y875F) alteration is located in exon 21 (coding exon 21) of the MRVI1 gene. This alteration results from a A to T substitution at nucleotide position 2624, causing the tyrosine (Y) at amino acid position 875 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.066	.;.;.;.;.;.;T;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.82	T;.;T;.;T;T;T;.
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.065	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.28	N;.;N;N;N;N;N;.
REVEL	Benign	0.041
Sift	Benign	0.40	T;.;T;T;T;T;T;.
Sift4G	Benign	0.45	T;T;T;T;T;T;T;T
Vest4		0.10
MVP		0.061
MPC		0.072
ClinPred		0.22	T
GERP RS		3.3
gMVP		0.098

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs748752897; hg19: chr11-10597994;