rs72805186

Variant names:

• chr5-157087178-G-A
• rs72805186
• NM_032782.5:c.830C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_032782.5(HAVCR2):​c.830C>T​(p.Pro277Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0111 in 1,613,956 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (9 hom., cov: 33)
  • Exomes 𝑓: 0.011 (122 hom.)
• Consequence: HAVCR2 NM_032782.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.59
• Publications: 9 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040649474).
• BP6: Variant 5-157087178-G-A is Benign according to our data. Variant chr5-157087178-G-A is described in ClinVar as Benign. ClinVar VariationId is 782945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 9 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.830C>T	p.Pro277Leu	missense	Exon 7 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.830C>T	p.Pro277Leu	missense	Exon 7 of 7	ENSP00000312002.4	Q8TDQ0-1
	HAVCR2	ENST00000696899.1		c.830C>T	p.Pro277Leu	missense	Exon 8 of 8	ENSP00000512960.1	Q8TDQ0-1
	HAVCR2	ENST00000853244.1		c.830C>T	p.Pro277Leu	missense	Exon 8 of 8	ENSP00000523303.1

Frequencies

GnomAD3 genomes AF: 0.00769 AC: 1170 AN: 152154 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00891

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00808 AC: 2029 AN: 251216 AF XY: 0.00840

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.00655

Gnomad ASJ exome AF: 0.00904

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00277

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.0115 AC: 16759 AN: 1461684 Hom.: 122 Cov.: 31 AF XY: 0.0114 AC XY: 8268 AN XY: 727154

African (AFR) AF: 0.00236 AC: 79 AN: 33464

American (AMR) AF: 0.00640 AC: 286 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00995 AC: 260 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00451 AC: 389 AN: 86236

European-Finnish (FIN) AF: 0.00328 AC: 175 AN: 53414

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5768

European-Non Finnish (NFE) AF: 0.0134 AC: 14937 AN: 1111912

Other (OTH) AF: 0.00980 AC: 592 AN: 60396

GnomAD4 genome AF: 0.00770 AC: 1172 AN: 152272 Hom.: 9 Cov.: 33 AF XY: 0.00709 AC XY: 528 AN XY: 74456

African (AFR) AF: 0.00236 AC: 98 AN: 41550

American (AMR) AF: 0.00890 AC: 136 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 28 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00602 AC: 29 AN: 4820

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0124 AC: 843 AN: 68030

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.0111 Hom.: 21

Bravo AF: 0.00852

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0161 AC: 62

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0151 AC: 130

ExAC AF: 0.00845 AC: 1026

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.0127

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	HAVCR2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Benign	0.95
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.6
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.092
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.011	D
Polyphen		0.74	P
Vest4		0.27
MVP		0.33
MPC		0.13
ClinPred		0.025	T
GERP RS		4.5
Varity_R		0.058
gMVP		0.61
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs72805186; hg19: chr5-156514189; COSMIC: COSV100325082;