Genetic Variant HAVCR1:p.Asn291Ser (chr5-157037327-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_001173393.3(HAVCR1):c.872A>G(p.Asn291Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,594,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

HAVCR1
NM_001173393.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.910

Variant links:

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]

HAVCR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity HAVR1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0877274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAVCR1	NM_001173393.3 link	c.872A>G	p.Asn291Ser	missense_variant	Exon 7 of 9	ENST00000523175.6	NP_001166864.1	Q96D42B4DPB1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HAVCR1	ENST00000523175.6 link	c.872A>G	p.Asn291Ser	missense_variant	Exon 7 of 9	1	NM_001173393.3	ENSP00000427898.1		Q96D42

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249198

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000104

AC:

AN:

1441920

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

718560

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000183

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.872A>G (p.N291S) alteration is located in exon 6 (coding exon 6) of the HAVCR1 gene. This alteration results from a A to G substitution at nucleotide position 872, causing the asparagine (N) at amino acid position 291 to be replaced by a serine (S). 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

0.071

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.049

DANN

Benign

0.94

DEOGEN2

Benign

0.019

T;.;.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.48

.;.;T;T

M_CAP

Benign

0.00094

MetaRNN

Benign

0.088

T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.72

N;N;N;.

REVEL

Benign

0.026

Sift

Uncertain

0.0080

D;T;T;.

Sift4G

Benign

0.20

T;T;T;T

Polyphen

0.0050

B;.;.;B

Vest4

0.22

MutPred

0.61

Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);Loss of loop (P = 0.0235);

MVP

0.085

MPC

0.25

ClinPred

0.097

GERP RS

-3.8

gMVP

0.052

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over