Variant chr1-39682545-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016257.4(HPCAL4):c.567G>A(p.Met189Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: 3.87

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.118952304).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPCAL4	NM_016257.4 linkuse as main transcript	c.567G>A	p.Met189Ile	missense_variant	4/4	ENST00000372844.8	NP_057341.1	Q9UM19
HPCAL4	NM_001282396.2 linkuse as main transcript	c.567G>A	p.Met189Ile	missense_variant	5/5		NP_001269325.1	Q9UM19
HPCAL4	NM_001282397.2 linkuse as main transcript	c.351G>A	p.Met117Ile	missense_variant	3/3		NP_001269326.1	B4DGW9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HPCAL4	ENST00000372844.8 linkuse as main transcript	c.567G>A	p.Met189Ile	missense_variant	4/4	1	NM_016257.4	ENSP00000361935.3	Q9UM19
HPCAL4	ENST00000617690.2 linkuse as main transcript	c.567G>A	p.Met189Ile	missense_variant	5/5	5		ENSP00000481834.1	Q9UM19
HPCAL4	ENST00000612703.3 linkuse as main transcript	c.351G>A	p.Met117Ile	missense_variant	3/3	2		ENSP00000484070.1	B4DGW9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251482

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

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

May 09, 2023

The c.567G>A (p.M189I) alteration is located in exon 4 (coding exon 3) of the HPCAL4 gene. This alteration results from a G to A substitution at nucleotide position 567, causing the methionine (M) at amino acid position 189 to be replaced by an isoleucine (I). 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

Benign

0.18

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.73

DEOGEN2

Benign

0.034

.;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.057

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

T;T;.

M_CAP

Benign

0.016

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.13

.;N;N

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.42

.;.;N

REVEL

Uncertain

0.30

Sift

Benign

1.0

.;.;T

Sift4G

Benign

0.73

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.27

MutPred

0.26

.;Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);

MVP

0.65

MPC

0.68

ClinPred

0.75

GERP RS

4.3

Varity_R

0.36

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over