1-39684142-T-C

Position:

• chr1-39684142-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016257.4(HPCAL4):​c.173A>G​(p.Tyr58Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HPCAL4 NM_016257.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

Genes affected

HPCAL4 (HGNC:18212): (hippocalcin like 4) The protein encoded by this gene is highly similar to human hippocalcin protein and hippocalcin like-1 protein. It also has similarity to rat neural visinin-like Ca2+-binding protein-type 1 and 2 proteins. This encoded protein may be involved in the calcium-dependent regulation of rhodopsin phosphorylation. The transcript of this gene has multiple polyadenylation sites. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPCAL4	NM_016257.4	c.173A>G	p.Tyr58Cys	missense_variant	3/4	ENST00000372844.8	NP_057341.1
HPCAL4	NM_001282396.2	c.173A>G	p.Tyr58Cys	missense_variant	4/5		NP_001269325.1
HPCAL4	NM_001282397.2	c.162+300A>G		intron_variant			NP_001269326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPCAL4	ENST00000372844.8	c.173A>G	p.Tyr58Cys	missense_variant	3/4	1	NM_016257.4	ENSP00000361935.3
HPCAL4	ENST00000617690.2	c.173A>G	p.Tyr58Cys	missense_variant	4/5	5		ENSP00000481834.1
HPCAL4	ENST00000612703.3	c.162+300A>G		intron_variant		2		ENSP00000484070.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2024

The c.173A>G (p.Y58C) alteration is located in exon 3 (coding exon 2) of the HPCAL4 gene. This alteration results from a A to G substitution at nucleotide position 173, causing the tyrosine (Y) at amino acid position 58 to be replaced by a cysteine (C). 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	Uncertain	0.43
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;.
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.8	L;L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.4	.;D
REVEL	Uncertain	0.38
Sift	Benign	0.042	.;D
Sift4G	Benign	0.17	T;T
Polyphen		0.99	D;D
Vest4		0.81
MutPred		0.39		Gain of catalytic residue at P57 (P = 0.0103);Gain of catalytic residue at P57 (P = 0.0103);
MVP		0.61
MPC		1.8
ClinPred		0.99	D
GERP RS		3.5
Varity_R		0.47
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1646652133; hg19: chr1-40149814;