NM_032782.5:c.512T>C

Variant names:

• chr5-157098868-A-G
• rs73815925
• NM_032782.5:c.512T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0053 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (2 hom.)
• Consequence: HAVCR2 NM_032782.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0420
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• subcutaneous panniculitis-like T-cell lymphoma

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• HAVCR2-related cancer predisposition

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 3041586.Status of the report is no_assertion_criteria_provided, 0 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032782.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAVCR2	NM_032782.5	MANE Select	c.512T>C	p.Ile171Thr	missense	Exon 4 of 7	NP_116171.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAVCR2	ENST00000307851.9	TSL:1 MANE Select	c.512T>C	p.Ile171Thr	missense	Exon 4 of 7	ENSP00000312002.4	Q8TDQ0-1
	HAVCR2	ENST00000521665.2	TSL:1	c.161T>C	p.Ile54Thr	missense	Exon 3 of 4	ENSP00000513314.1	A0A8V8TMM7
	HAVCR2	ENST00000696899.1		c.512T>C	p.Ile171Thr	missense	Exon 5 of 8	ENSP00000512960.1	Q8TDQ0-1

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

GnomAD2 exomes AF: 0.00138 AC: 347 AN: 251026 AF XY: 0.000995

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 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

African (AFR) AF: 0.0190 AC: 636 AN: 33440

American (AMR) AF: 0.000784 AC: 35 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111362

Other (OTH) AF: 0.00113 AC: 68 AN: 60360

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

African (AFR) AF: 0.0186 AC: 774 AN: 41574

American (AMR) AF: 0.00144 AC: 22 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00124 Hom.: 2

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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HAVCR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.042
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.0070
Sift	Benign	0.42	T
Sift4G	Benign	0.57	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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs73815925; hg19: chr5-156525879; COSMIC: COSV99074220;