7-150742750-T-C

Position:

chr7-150742750-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4B:1

Conservation

PhyloP100: 3.20

Variant links:

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]

GIMAP5 links:

GIMAP1-GIMAP5 (HGNC:):

GIMAP1-GIMAP5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
GIMAP5	NM_018384.5 linkuse as main transcript	c.611T>C	p.Leu204Pro	missense_variant	3/3	ENST00000358647.5
GIMAP1-GIMAP5	NM_001199577.2 linkuse as main transcript	c.1223T>C	p.Leu408Pro	missense_variant	6/6
GIMAP1-GIMAP5	NM_001303630.2 linkuse as main transcript	c.839T>C	p.Leu280Pro	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GIMAP5	ENST00000358647.5 linkuse as main transcript	c.611T>C	p.Leu204Pro	missense_variant	3/3	1	NM_018384.5	P1	Q96F15-1

Frequencies

GnomAD3 genomes

AF:

0.00188

AC:

286

AN:

152182

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00198

AC XY:

269

AN XY:

135678

show subpopulations

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.:

Cov.:

AF XY:

0.00298

AC XY:

2166

AN XY:

727244

show subpopulations

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.:

Cov.:

AF XY:

0.00180

AC XY:

134

AN XY:

74470

show subpopulations

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.:

Bravo

AF:

0.00161

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00361

AC:

ExAC

AF:

0.00207

AC:

251

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00333

EpiControl

AF:

0.00338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

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

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

.;T;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.58

T;.;T

M_CAP

Benign

0.0046

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.2

.;M;M

MutationTaster

Benign

0.98

PrimateAI

Benign

0.44

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over