5-157052415-T-G

Variant names:

• chr5-157052415-T-G
• rs12522248
• NM_001173393.3:c.619A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001173393.3(HAVCR1):​c.619A>C​(p.Thr207Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T207A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HAVCR1 NM_001173393.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.709
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06959152).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173393.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAVCR1	NM_001173393.3	MANE Select	c.619A>C	p.Thr207Pro	missense	Exon 4 of 9	NP_001166864.1
	HAVCR1	NM_001308156.2		c.619A>C	p.Thr207Pro	missense	Exon 4 of 8	NP_001295085.1
	HAVCR1	NM_012206.3		c.619A>C	p.Thr207Pro	missense	Exon 3 of 8	NP_036338.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HAVCR1	ENST00000523175.6	TSL:1 MANE Select	c.619A>C	p.Thr207Pro	missense	Exon 4 of 9	ENSP00000427898.1
	HAVCR1	ENST00000339252.8	TSL:1	c.619A>C	p.Thr207Pro	missense	Exon 3 of 8	ENSP00000344844.3
	HAVCR1	ENST00000522693.5	TSL:2	c.619A>C	p.Thr207Pro	missense	Exon 4 of 8	ENSP00000428524.1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461662 Hom.: 0 Cov.: 48 AF XY: 0.00 AC XY: 0 AN XY: 727152

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111818

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 35

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	1.2
DANN	Benign	0.38
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.71
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.13
Sift	Benign	0.21	T
Sift4G	Benign	0.13	T
Polyphen		0.33	B
Vest4		0.11
MutPred		0.27		Loss of sheet (P = 0.007)
MVP		0.14
MPC		0.25
ClinPred		0.26	T
GERP RS		1.1
gMVP		0.11
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs12522248; hg19: chr5-156479426;