5-157052498-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001173393.3(HAVCR1):c.536T>C(p.Leu179Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.857 in 1,613,744 control chromosomes in the GnomAD database, including 594,062 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.87 (57328 hom., cov: 33)
  • Exomes 𝑓: 0.86 (536734 hom.)
• Consequence: HAVCR1 NM_001173393.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.35

Genes affected

HAVCR1 (HGNC:17866): (hepatitis A virus cellular receptor 1) The protein encoded by this gene is a membrane receptor for both human hepatitis A virus (HHAV) and TIMD4. The encoded protein may be involved in the moderation of asthma and allergic diseases. The reference genome represents an allele that retains a MTTVP amino acid segment that confers protection against atopy in HHAV seropositive individuals. The protein is a receptor for multiple other viruses, including Ebola virus, Marburg virus, Dengue virus, and Zika virus and is a possible entry factor for SARS-CoV-2 and other coronaviruses. [provided by RefSeq, Sep 2021]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1887994E-6).
• BP6: Variant 5-157052498-A-G is Benign according to our data. Variant chr5-157052498-A-G is described in ClinVar as [Benign]. Clinvar id is 3059144.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.965 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAVCR1	NM_001173393.3	c.536T>C	p.Leu179Pro	missense_variant	4/9	ENST00000523175.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAVCR1	ENST00000523175.6	c.536T>C	p.Leu179Pro	missense_variant	4/9	1	NM_001173393.3	P2

Frequencies

GnomAD3 genomes AF: 0.868 AC: 131782 AN: 151798 Hom.: 57277 Cov.: 33

Gnomad AFR AF: 0.875

Gnomad AMI AF: 0.982

Gnomad AMR AF: 0.911

Gnomad ASJ AF: 0.907

Gnomad EAS AF: 0.987

Gnomad SAS AF: 0.950

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.838

Gnomad OTH AF: 0.874

GnomAD3 exomes AF: 0.884 AC: 220772 AN: 249610 Hom.: 98031 AF XY: 0.886 AC XY: 119984 AN XY: 135410

Gnomad AFR exome AF: 0.880

Gnomad AMR exome AF: 0.936

Gnomad ASJ exome AF: 0.902

Gnomad EAS exome AF: 0.990

Gnomad SAS exome AF: 0.956

Gnomad FIN exome AF: 0.846

Gnomad NFE exome AF: 0.840

Gnomad OTH exome AF: 0.869

GnomAD4 exome AF: 0.856 AC: 1251008 AN: 1461828 Hom.: 536734 Cov.: 63 AF XY: 0.858 AC XY: 624291 AN XY: 727208

Gnomad4 AFR exome AF: 0.878

Gnomad4 AMR exome AF: 0.932

Gnomad4 ASJ exome AF: 0.904

Gnomad4 EAS exome AF: 0.982

Gnomad4 SAS exome AF: 0.954

Gnomad4 FIN exome AF: 0.846

Gnomad4 NFE exome AF: 0.839

Gnomad4 OTH exome AF: 0.865

GnomAD4 genome AF: 0.868 AC: 131890 AN: 151916 Hom.: 57328 Cov.: 33 AF XY: 0.872 AC XY: 64738 AN XY: 74264

Gnomad4 AFR AF: 0.875

Gnomad4 AMR AF: 0.911

Gnomad4 ASJ AF: 0.907

Gnomad4 EAS AF: 0.987

Gnomad4 SAS AF: 0.950

Gnomad4 FIN AF: 0.856

Gnomad4 NFE AF: 0.838

Gnomad4 OTH AF: 0.874

Alfa AF: 0.854 Hom.: 87809

Bravo AF: 0.873

TwinsUK AF: 0.845 AC: 3135

ALSPAC AF: 0.840 AC: 3239

ESP6500AA AF: 0.881 AC: 3746

ESP6500EA AF: 0.840 AC: 7110

ExAC AF: 0.884 AC: 107012

Asia WGS AF: 0.957 AC: 3330 AN: 3478

EpiCase AF: 0.847

EpiControl AF: 0.845

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HAVCR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 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	0.044
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.14
Dann	Benign	0.077
DEOGEN2	Benign	0.0069	T;.;.;T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00048	N
MetaRNN	Benign	0.0000012	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.20	T
PROVEAN	Benign	2.5	N;N;N;.;N
REVEL	Benign	0.017
Sift	Benign	0.25	T;T;T;.;T
Sift4G	Benign	0.23	T;T;T;T;T
Polyphen		0.0	B;.;.;B;.
Vest4		0.022
MPC		0.31
ClinPred		0.0022	T
GERP RS		-2.3
gMVP		0.080

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: rs1553316; hg19: chr5-156479509; COSMIC: COSV59402931; COSMIC: COSV59402931;