rs35960726

Positions:

• chr5-157106730-T-C

Variant summary

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

The NM_032782.5(HAVCR2):​c.291A>G​(p.Ile97Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,614,234 control chromosomes in the GnomAD database, including 18 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 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (18 hom.)
• Consequence: HAVCR2 NM_032782.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 B:1 O:1
• Conservation: PhyloP100: -0.454

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0537073).
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAVCR2	NM_032782.5	c.291A>G	p.Ile97Met	missense_variant	2/7	ENST00000307851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAVCR2	ENST00000307851.9	c.291A>G	p.Ile97Met	missense_variant	2/7	1	NM_032782.5	P2
	ENST00000517708.1	n.147+1796T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 392 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00606

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00476

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00266 AC: 668 AN: 251442 Hom.: 0 AF XY: 0.00247 AC XY: 335 AN XY: 135896

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00448

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00253 AC: 3698 AN: 1461884 Hom.: 18 Cov.: 30 AF XY: 0.00258 AC XY: 1874 AN XY: 727246

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.00293

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00257 AC: 392 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.00231 AC XY: 172 AN XY: 74508

Gnomad4 AFR AF: 0.000240

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00606

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00476

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00411 Hom.: 6

Bravo AF: 0.00215

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00395 AC: 34

ExAC AF: 0.00290 AC: 352

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00350

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	HAVCR2: BP4, BS1:Supporting -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 30374066, 32005988, 32285995, 34426522, 36278991, 36113963, 34159709, 36291756, 35588499, 35725860) -

Subcutaneous panniculitis-like T-cell lymphoma Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 21, 2019	This variant was identified as homozygous -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
risk factor, no assertion criteria provided	literature only	OMIM	Apr 12, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.037
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.6	H;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.88
MVP		0.63
MPC		0.60
ClinPred		0.10	T
GERP RS		2.9
Varity_R		0.80
gMVP		0.68

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: rs35960726; hg19: chr5-156533741;