5-157052513-G-A

Variant summary

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

The NM_001173393.3(HAVCR1):c.521C>T(p.Thr174Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,601,450 control chromosomes in the GnomAD database, including 61 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T174K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (34 hom., cov: 35)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: HAVCR1 NM_001173393.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.12

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=0.0030674934).
• BP6: Variant 5-157052513-G-A is Benign according to our data. Variant chr5-157052513-G-A is described in ClinVar as [Benign]. Clinvar id is 3039113.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0105 (1600/151978) while in subpopulation AFR AF= 0.0369 (1527/41372). AF 95% confidence interval is 0.0354. There are 34 homozygotes in gnomad4. There are 732 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAVCR1	NM_001173393.3	c.521C>T	p.Thr174Met	missense_variant	4/9	ENST00000523175.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAVCR1	ENST00000523175.6	c.521C>T	p.Thr174Met	missense_variant	4/9	1	NM_001173393.3	P2

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1600 AN: 151858 Hom.: 34 Cov.: 35

Gnomad AFR AF: 0.0370

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00815

GnomAD3 exomes AF: 0.00269 AC: 671 AN: 249610 Hom.: 12 AF XY: 0.00210 AC XY: 285 AN XY: 135412

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000334

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00107 AC: 1546 AN: 1449472 Hom.: 27 Cov.: 63 AF XY: 0.000928 AC XY: 669 AN XY: 720882

Gnomad4 AFR exome AF: 0.0374

Gnomad4 AMR exome AF: 0.00204

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000178

Gnomad4 SAS exome AF: 0.000106

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000598

Gnomad4 OTH exome AF: 0.00219

GnomAD4 genome AF: 0.0105 AC: 1600 AN: 151978 Hom.: 34 Cov.: 35 AF XY: 0.00985 AC XY: 732 AN XY: 74322

Gnomad4 AFR AF: 0.0369

Gnomad4 AMR AF: 0.00302

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00105 Hom.: 1

Bravo AF: 0.0119

ESP6500AA AF: 0.0379 AC: 161

ESP6500EA AF: 0.000589 AC: 5

ExAC AF: 0.00338 AC: 409

EpiCase AF: 0.000109

EpiControl AF: 0.000178

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

Sep 11, 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	0.084
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	8.6
Dann	Benign	0.86
DEOGEN2	Benign	0.028	T;.;.;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.21	N
MetaRNN	Benign	0.0031	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.60	N;N;N;.;N
REVEL	Benign	0.090
Sift	Benign	0.065	T;T;T;.;T
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		1.0	D;.;.;D;.
Vest4		0.17
MVP		0.28
MPC		0.20
ClinPred		0.0039	T
GERP RS		1.0
gMVP		0.22

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: rs61734035; hg19: chr5-156479524; COSMIC: COSV59400077; COSMIC: COSV59400077;