rs12522248

chr5-157052415-T-C

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.619A>G(p.Thr207Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.282 in 1,610,364 control chromosomes in the GnomAD database, including 66,117 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. T207T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.26 (5425 hom., cov: 35)
  • Exomes 𝑓: 0.28 (60692 hom.)
• Consequence: HAVCR1 NM_001173393.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.709

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=0.0026894212).
• BP6: Variant 5-157052415-T-C is Benign according to our data. Variant chr5-157052415-T-C is described in ClinVar as [Benign]. Clinvar id is 3060126.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAVCR1	NM_001173393.3	c.619A>G	p.Thr207Ala	missense_variant	4/9	ENST00000523175.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAVCR1	ENST00000523175.6	c.619A>G	p.Thr207Ala	missense_variant	4/9	1	NM_001173393.3	P2

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39111 AN: 149146 Hom.: 5421 Cov.: 35

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.306

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.299

GnomAD3 exomes AF: 0.288 AC: 71875 AN: 249582 Hom.: 11232 AF XY: 0.285 AC XY: 38624 AN XY: 135404

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.305

Gnomad EAS exome AF: 0.159

Gnomad SAS exome AF: 0.267

Gnomad FIN exome AF: 0.271

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.301

GnomAD4 exome AF: 0.284 AC: 415086 AN: 1461116 Hom.: 60692 Cov.: 48 AF XY: 0.284 AC XY: 206123 AN XY: 726886

Gnomad4 AFR exome AF: 0.164

Gnomad4 AMR exome AF: 0.420

Gnomad4 ASJ exome AF: 0.305

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.266

Gnomad4 FIN exome AF: 0.270

Gnomad4 NFE exome AF: 0.290

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.262 AC: 39124 AN: 149248 Hom.: 5425 Cov.: 35 AF XY: 0.263 AC XY: 19145 AN XY: 72866

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.273

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.291

Gnomad4 OTH AF: 0.296

Alfa AF: 0.285 Hom.: 13393

Bravo AF: 0.261

TwinsUK AF: 0.291 AC: 1078

ALSPAC AF: 0.291 AC: 1120

ESP6500AA AF: 0.170 AC: 698

ESP6500EA AF: 0.285 AC: 2393

ExAC AF: 0.279 AC: 33713

EpiCase AF: 0.303

EpiControl AF: 0.301

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

HAVCR1-related condition 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	0.074
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.28
Dann	Benign	0.18
DEOGEN2	Benign	0.0064	T;.;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.070	N
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.27	N;N;N;.;N
REVEL	Benign	0.12
Sift	Benign	0.55	T;T;T;.;T
Sift4G	Benign	0.46	T;T;T;T;T
Polyphen		0.015	B;.;.;B;.
Vest4		0.025
MPC		0.19
ClinPred		0.011	T
GERP RS		1.1
gMVP		0.11

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: rs12522248; hg19: chr5-156479426; COSMIC: COSV59398314; COSMIC: COSV59398314;