5-157052481-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001173393.3(HAVCR1):c.553T>C(p.Ser185Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,602,904 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. S185S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00031 (1 hom.)
• Consequence: HAVCR1 NM_001173393.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.69

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026841193).
• BP6: Variant 5-157052481-A-G is Benign according to our data. Variant chr5-157052481-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2458803.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HAVCR1	NM_001173393.3	c.553T>C	p.Ser185Pro	missense_variant	4/9	ENST00000523175.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HAVCR1	ENST00000523175.6	c.553T>C	p.Ser185Pro	missense_variant	4/9	1	NM_001173393.3	P2

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152142 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000373 AC: 93 AN: 249582 Hom.: 0 AF XY: 0.000384 AC XY: 52 AN XY: 135394

Gnomad AFR exome AF: 0.0000645

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.000644

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000311 AC: 451 AN: 1450762 Hom.: 1 Cov.: 53 AF XY: 0.000342 AC XY: 247 AN XY: 721534

Gnomad4 AFR exome AF: 0.0000605

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.000777

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.000527

Gnomad4 NFE exome AF: 0.000350

Gnomad4 OTH exome AF: 0.000200

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152142 Hom.: 0 Cov.: 35 AF XY: 0.000390 AC XY: 29 AN XY: 74310

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000554 Hom.: 0

Bravo AF: 0.000287

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000545

EpiControl AF: 0.000474

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.20
Dann	Benign	0.42
DEOGEN2	Benign	0.0049	T;.;.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0026	N
M_CAP	Benign	0.00061	T
MetaRNN	Benign	0.027	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	1.0	N;N;N;.;N
REVEL	Benign	0.015
Sift	Benign	0.21	T;T;T;.;T
Sift4G	Benign	0.32	T;T;T;T;T
Polyphen		0.0	B;.;.;B;.
Vest4		0.046
MVP		0.061
MPC		0.25
ClinPred		0.0051	T
GERP RS		-3.2
gMVP		0.10

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: rs200904360; hg19: chr5-156479492; COSMIC: COSV59404405; COSMIC: COSV59404405;