Variant chr1-39683990-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_016257.4(HPCAL4):c.325G>C(p.Asp109His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D109A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HPCAL4
NM_016257.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.86

Variant links:

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]

HPCAL4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity HPCL4_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPCAL4	NM_016257.4 linkuse as main transcript	c.325G>C	p.Asp109His	missense_variant	3/4	ENST00000372844.8	NP_057341.1	Q9UM19
HPCAL4	NM_001282396.2 linkuse as main transcript	c.325G>C	p.Asp109His	missense_variant	4/5		NP_001269325.1	Q9UM19
HPCAL4	NM_001282397.2 linkuse as main transcript	c.162+452G>C		intron_variant			NP_001269326.1	B4DGW9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HPCAL4	ENST00000372844.8 linkuse as main transcript	c.325G>C	p.Asp109His	missense_variant	3/4	1	NM_016257.4	ENSP00000361935.3	Q9UM19
HPCAL4	ENST00000617690.2 linkuse as main transcript	c.325G>C	p.Asp109His	missense_variant	4/5	5		ENSP00000481834.1	Q9UM19
HPCAL4	ENST00000612703.3 linkuse as main transcript	c.162+452G>C		intron_variant		2		ENSP00000484070.1	B4DGW9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461640

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2024

The c.325G>C (p.D109H) alteration is located in exon 3 (coding exon 2) of the HPCAL4 gene. This alteration results from a G to C substitution at nucleotide position 325, causing the aspartic acid (D) at amino acid position 109 to be replaced by a histidine (H). 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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;.

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.8

H;H

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.8

.;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.93

Gain of catalytic residue at D109 (P = 0.1324);Gain of catalytic residue at D109 (P = 0.1324);

MVP

0.98

MPC

1.7

ClinPred

1.0

GERP RS

3.5

Varity_R

0.93

gMVP

0.98

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over