5-157098871-T-A

Position:

• chr5-157098871-T-A

Variant summary

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

The NM_032782.5(HAVCR2):​c.509A>T​(p.Asp170Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000197 in 1,613,122 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (3 hom.)
• Consequence: HAVCR2 NM_032782.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:3
• Conservation: PhyloP100: 0.0410

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]

HAVCR2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005814433).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HAVCR2	NM_032782.5	c.509A>T	p.Asp170Val	missense_variant	4/7	ENST00000307851.9	NP_116171.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HAVCR2	ENST00000307851.9	c.509A>T	p.Asp170Val	missense_variant	4/7	1	NM_032782.5	ENSP00000312002.4

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000339 AC: 85 AN: 250988 Hom.: 1 AF XY: 0.000258 AC XY: 35 AN XY: 135640

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.00398

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000194

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000189 AC: 276 AN: 1460908 Hom.: 3 Cov.: 30 AF XY: 0.000194 AC XY: 141 AN XY: 726786

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00379

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000999

Gnomad4 OTH exome AF: 0.000514

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74416

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000390 Hom.: 0

Bravo AF: 0.000382

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 06, 2023

The c.509A>T (p.D170V) alteration is located in exon 4 (coding exon 4) of the HAVCR2 gene. This alteration results from a A to T substitution at nucleotide position 509, causing the aspartic acid (D) at amino acid position 170 to be replaced by a valine (V). 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	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.015	T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0058	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N;N;D
REVEL	Benign	0.19
Sift	Benign	0.032	D;T;D
Sift4G	Uncertain	0.0040	D;T;.
Polyphen		0.98	D;.;.
Vest4		0.43
MVP		0.51
MPC		0.42
ClinPred		0.056	T
GERP RS		5.0
Varity_R		0.17
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs182081536; hg19: chr5-156525882;