7-150720518-C-T

Position:

• chr7-150720518-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_130759.4(GIMAP1):​c.514C>T​(p.Arg172Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000069 in 1,448,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: GIMAP1 NM_130759.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.176

Genes affected

GIMAP1 (HGNC:23237): (GTPase, IMAP family member 1) This gene encodes a protein belonging to the GTP-binding superfamily and to the immuno-associated nucleotide (IAN) subfamily of nucleotide-binding proteins. In humans, the IAN subfamily genes are located in a cluster at 7q36.1. This gene is thought to be involved in the differentiation of T helper (Th) cells of the Th1 lineage, and the related mouse gene has been shown to be critical for the development of mature B and T lymphocytes. Read-through transcription exists between this gene and the downstream GIMAP5 (GTPase, IMAP family member 5) gene. [provided by RefSeq, Dec 2010]

GIMAP1-GIMAP5 (HGNC:51257): (GIMAP1-GIMAP5 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring GIMAP1 (GTPase, IMAP family member 1) and GIMAP5 (GTPase, IMAP family member 5) genes on chromosome 7. Alternative splicing results in multiple readthrough transcript variants, one of which encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26160735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GIMAP1	NM_130759.4	c.514C>T	p.Arg172Trp	missense_variant	3/3	ENST00000307194.6	NP_570115.1
GIMAP1-GIMAP5	NM_001199577.2	c.402+112C>T		intron_variant			NP_001186506.1
GIMAP1-GIMAP5	NM_001303630.2	c.18+1428C>T		intron_variant			NP_001290559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GIMAP1	ENST00000307194.6	c.514C>T	p.Arg172Trp	missense_variant	3/3	1	NM_130759.4	ENSP00000302833.5
GIMAP1-GIMAP5	ENST00000611999.4	c.402+112C>T		intron_variant		5		ENSP00000477920.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000690 AC: 10 AN: 1448932 Hom.: 0 Cov.: 31 AF XY: 0.00000973 AC XY: 7 AN XY: 719636

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000723

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 13, 2024

The c.514C>T (p.R172W) alteration is located in exon 3 (coding exon 2) of the GIMAP1 gene. This alteration results from a C to T substitution at nucleotide position 514, causing the arginine (R) at amino acid position 172 to be replaced by a tryptophan (W). 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	0.15
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.077
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.9	M
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.12
Sift	Benign	0.050	D
Sift4G	Benign	0.094	T
Polyphen		1.0	D
Vest4		0.21
MutPred		0.49		Loss of disorder (P = 0.0184);
MVP		0.43
MPC		1.7
ClinPred		0.85	D
GERP RS		1.7
Varity_R		0.29
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs1417844598; hg19: chr7-150417606; COSMIC: COSV100212349; COSMIC: COSV100212349;