5-157098868-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_032782.5(HAVCR2):c.512T>C(p.Ile171Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000973 in 1,613,236 control chromosomes in the GnomAD database, including 12 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0053 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (2 hom.)
• Consequence: HAVCR2 NM_032782.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0420

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034349859).
• BP6: Variant 5-157098868-A-G is Benign according to our data. Variant chr5-157098868-A-G is described in ClinVar as [Benign]. Clinvar id is 3041586.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00532 (810/152322) while in subpopulation AFR AF= 0.0186 (774/41574). AF 95% confidence interval is 0.0175. There are 10 homozygotes in gnomad4. There are 356 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAVCR2	NM_032782.5	c.512T>C	p.Ile171Thr	missense_variant	4/7	ENST00000307851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAVCR2	ENST00000307851.9	c.512T>C	p.Ile171Thr	missense_variant	4/7	1	NM_032782.5	P2

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 809 AN: 152204 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00527

GnomAD3 exomes AF: 0.00138 AC: 347 AN: 251026 Hom.: 0 AF XY: 0.000995 AC XY: 135 AN XY: 135664

Gnomad AFR exome AF: 0.0196

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000520 AC: 759 AN: 1460914 Hom.: 2 Cov.: 29 AF XY: 0.000444 AC XY: 323 AN XY: 726798

Gnomad4 AFR exome AF: 0.0190

Gnomad4 AMR exome AF: 0.000784

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00532 AC: 810 AN: 152322 Hom.: 10 Cov.: 32 AF XY: 0.00478 AC XY: 356 AN XY: 74492

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.000981 Hom.: 1

Bravo AF: 0.00611

ESP6500AA AF: 0.0188 AC: 83

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00178 AC: 216

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HAVCR2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	2.2
Dann	Benign	0.24
DEOGEN2	Benign	0.00072	T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.33	T;T;T
MetaRNN	Benign	0.0034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.1	N;N;N
REVEL	Benign	0.0070
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.57	T;T;.
Polyphen		0.0020	B;.;.
Vest4		0.073
MVP		0.072
MPC		0.17
ClinPred		0.0037	T
GERP RS		-1.7
Varity_R		0.030
gMVP		0.099

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs73815925; hg19: chr5-156525879; COSMIC: COSV99074220;