rs1036199

Positions:

• chr5-157104725-C-A
• chr5-157104725-C-G
• chr5-157104725-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032782.5(HAVCR2):​c.419G>T​(p.Arg140Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.834 in 1,600,776 control chromosomes in the GnomAD database, including 558,802 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.83 (53089 hom., cov: 33)
  • Exomes 𝑓: 0.83 (505713 hom.)
• Consequence: HAVCR2 NM_032782.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.202

Genes affected

HAVCR2 (HGNC:18437): (hepatitis A virus cellular receptor 2) The protein encoded by this gene belongs to the immunoglobulin superfamily, and TIM family of proteins. CD4-positive T helper lymphocytes can be divided into types 1 (Th1) and 2 (Th2) on the basis of their cytokine secretion patterns. Th1 cells are involved in cell-mediated immunity to intracellular pathogens and delayed-type hypersensitivity reactions, whereas, Th2 cells are involved in the control of extracellular helminthic infections and the promotion of atopic and allergic diseases. This protein is a Th1-specific cell surface protein that regulates macrophage activation, and inhibits Th1-mediated auto- and alloimmune responses, and promotes immunological tolerance. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.7537273E-7).
• BP6: Variant 5-157104725-C-A is Benign according to our data. Variant chr5-157104725-C-A is described in ClinVar as [Benign]. Clinvar id is 1285330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAVCR2	NM_032782.5	c.419G>T	p.Arg140Leu	missense_variant	3/7	ENST00000307851.9	NP_116171.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAVCR2	ENST00000307851.9	c.419G>T	p.Arg140Leu	missense_variant	3/7	1	NM_032782.5	ENSP00000312002.4

Frequencies

GnomAD3 genomes AF: 0.834 AC: 126877 AN: 152096 Hom.: 53052 Cov.: 33

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.898

Gnomad AMR AF: 0.887

Gnomad ASJ AF: 0.888

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.952

Gnomad FIN AF: 0.853

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.816

Gnomad OTH AF: 0.838

GnomAD3 exomes AF: 0.865 AC: 203321 AN: 234978 Hom.: 88469 AF XY: 0.868 AC XY: 109633 AN XY: 126330

Gnomad AFR exome AF: 0.806

Gnomad AMR exome AF: 0.924

Gnomad ASJ exome AF: 0.883

Gnomad EAS exome AF: 0.989

Gnomad SAS exome AF: 0.952

Gnomad FIN exome AF: 0.839

Gnomad NFE exome AF: 0.815

Gnomad OTH exome AF: 0.850

GnomAD4 exome AF: 0.834 AC: 1208317 AN: 1448562 Hom.: 505713 Cov.: 34 AF XY: 0.837 AC XY: 602396 AN XY: 719370

Gnomad4 AFR exome AF: 0.802

Gnomad4 AMR exome AF: 0.919

Gnomad4 ASJ exome AF: 0.883

Gnomad4 EAS exome AF: 0.983

Gnomad4 SAS exome AF: 0.951

Gnomad4 FIN exome AF: 0.838

Gnomad4 NFE exome AF: 0.816

Gnomad4 OTH exome AF: 0.846

GnomAD4 genome AF: 0.834 AC: 126972 AN: 152214 Hom.: 53089 Cov.: 33 AF XY: 0.840 AC XY: 62552 AN XY: 74438

Gnomad4 AFR AF: 0.801

Gnomad4 AMR AF: 0.887

Gnomad4 ASJ AF: 0.888

Gnomad4 EAS AF: 0.987

Gnomad4 SAS AF: 0.952

Gnomad4 FIN AF: 0.853

Gnomad4 NFE AF: 0.816

Gnomad4 OTH AF: 0.840

Alfa AF: 0.828 Hom.: 116418

Bravo AF: 0.836

TwinsUK AF: 0.818 AC: 3034

ALSPAC AF: 0.814 AC: 3136

ESP6500AA AF: 0.811 AC: 3573

ESP6500EA AF: 0.813 AC: 6994

ExAC AF: 0.857 AC: 103696

Asia WGS AF: 0.955 AC: 3321 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Subcutaneous panniculitis-like T-cell lymphoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 94. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	3.9
DANN	Benign	0.68
DEOGEN2	Benign	0.0016	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.20	T;T
MetaRNN	Benign	8.8e-7	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.030	N;N
REVEL	Benign	0.019
Sift	Benign	0.47	T;T
Sift4G	Benign	0.37	T;.
Polyphen		0.0	B;.
Vest4		0.015
MPC		0.16
ClinPred		0.0017	T
GERP RS		-0.064
Varity_R		0.040
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1036199; hg19: chr5-156531736;