chr7-150742750-T-C

Position:

• chr7-150742750-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018384.5(GIMAP5):​c.611T>C​(p.Leu204Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,614,186 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (10 hom.)
• Consequence: GIMAP5 NM_018384.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 B:1
• Conservation: PhyloP100: 3.20

Genes affected

GIMAP5 (HGNC:18005): (GTPase, IMAP family member 5) 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 encodes an antiapoptotic protein that functions in T-cell survival. Polymorphisms in this gene are associated with systemic lupus erythematosus. Read-through transcription exists between this gene and the neighboring upstream GIMAP1 (GTPase, IMAP family member 1) gene. [provided by RefSeq, Dec 2010]

GIMAP1-GIMAP5 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019603252).
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GIMAP5	NM_018384.5	c.611T>C	p.Leu204Pro	missense_variant	3/3	ENST00000358647.5	NP_060854.2
GIMAP1-GIMAP5	NM_001199577.2	c.1223T>C	p.Leu408Pro	missense_variant	6/6		NP_001186506.1
GIMAP1-GIMAP5	NM_001303630.2	c.839T>C	p.Leu280Pro	missense_variant	5/5		NP_001290559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GIMAP5	ENST00000358647.5	c.611T>C	p.Leu204Pro	missense_variant	3/3	1	NM_018384.5	ENSP00000351473	P1

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00317

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00204 AC: 512 AN: 251010 Hom.: 1 AF XY: 0.00198 AC XY: 269 AN XY: 135678

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00294

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00291 AC: 4249 AN: 1461886 Hom.: 10 Cov.: 73 AF XY: 0.00298 AC XY: 2166 AN XY: 727244

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.00332

Gnomad4 OTH exome AF: 0.00228

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74470

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00318

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00243 Hom.: 1

Bravo AF: 0.00161

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00361 AC: 31

ExAC AF: 0.00207 AC: 251

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Portal hypertension, noncirrhotic, 2 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 02, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 04, 2024	Variant summary: GIMAP5 c.611T>C (p.Leu204Pro) results in a non-conservative amino acid change located in the AIG1-type guanine nucleotide-binding (G) domain (IPR006703) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 251010 control chromosomes in the gnomAD database, including 1 homozygotes. c.611T>C has been reported in the literature in a homozygous individuals affected with GIMAP5-associated hypertension. T cells isolated from this patient had complete loss of GIMAP5 protein expression, reduced T cell proliferation which was restored upon pharmacological targeting of GSK3. (example: Patterson_2018, and Drewieck_GIMAP5_JEM_2021). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33956074, 29382851, 35753512).Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=2) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Feb 14, 2023	The missense c.611T>C (p.Leu204Pro) in GIMAP5 gene has been reported previously in homozygous state in individuals affected with GIMAP5-associated hypertension (Patterson et al. 2018; Drzewiecki et al. 2021). Experimental studies demonstrated an undetectable protein expression of both GIMAP5 isoforms for this variant (Patterson et al. 2018). This variant is reported with an allele frequency of 0.2% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic. The amino acid change p.Leu204Pro in GIMAP5 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 204 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Portal hypertension Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Yale Center for Mendelian Genomics, Yale University

May 06, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

GIMAP1-GIMAP5: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.58	T;.;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.2	.;M;M
MutationTaster	Benign	0.98	D
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-4.1	.;.;D
REVEL	Benign	0.20
Sift	Uncertain	0.0020	.;.;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.48
MVP		0.54
MPC		0.19
ClinPred		0.066	T
GERP RS		3.1
Varity_R		0.82
gMVP		0.76

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: rs72650695; hg19: chr7-150439838;