chr1-39684540-A-G

Position:

chr1-39684540-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP3BP4

The NM_016257.4(HPCAL4):c.64T>C(p.Phe22Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 1,613,156 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

HPCAL4
NM_016257.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.18

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN [when max_spliceai, FATHMM_MKL, M_CAP, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.29445547).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPCAL4	NM_016257.4 linkuse as main transcript	c.64T>C	p.Phe22Leu	missense_variant	2/4	ENST00000372844.8	NP_057341.1	Q9UM19
HPCAL4	NM_001282396.2 linkuse as main transcript	c.64T>C	p.Phe22Leu	missense_variant	3/5		NP_001269325.1	Q9UM19
HPCAL4	NM_001282397.2 linkuse as main transcript	c.64T>C	p.Phe22Leu	missense_variant	2/3		NP_001269326.1	B4DGW9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HPCAL4	ENST00000372844.8 linkuse as main transcript	c.64T>C	p.Phe22Leu	missense_variant	2/4	1	NM_016257.4	ENSP00000361935.3	Q9UM19
HPCAL4	ENST00000617690.2 linkuse as main transcript	c.64T>C	p.Phe22Leu	missense_variant	3/5	5		ENSP00000481834.1	Q9UM19
HPCAL4	ENST00000612703.3 linkuse as main transcript	c.64T>C	p.Phe22Leu	missense_variant	2/3	2		ENSP00000484070.1	B4DGW9

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

151888

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000959

GnomAD3 exomes

AF:

0.000236

AC:

AN:

250302

Hom.:

AF XY:

0.000251

AC XY:

AN XY:

135342

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00250

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000257

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000213

AC:

311

AN:

1461150

Hom.:

Cov.:

AF XY:

0.000224

AC XY:

163

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00303

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000187

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.000151

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000949

Alfa

AF:

0.000290

Hom.:

Bravo

AF:

0.000208

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000231

AC:

EpiCase

AF:

0.000437

EpiControl

AF:

0.000237

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

Oct 13, 2023

The c.64T>C (p.F22L) alteration is located in exon 2 (coding exon 1) of the HPCAL4 gene. This alteration results from a T to C substitution at nucleotide position 64, causing the phenylalanine (F) at amino acid position 22 to be replaced by a leucine (L). 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

Uncertain

0.046

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

.;T;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;.

M_CAP

Benign

0.077

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Uncertain

0.043

MutationAssessor

Pathogenic

3.1

.;M;M

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.4

.;.;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0030

.;.;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.88

P;B;B

Vest4

0.76

MutPred

0.58

Gain of disorder (P = 0.0863);Gain of disorder (P = 0.0863);Gain of disorder (P = 0.0863);

MVP

0.82

MPC

0.72

ClinPred

0.78

GERP RS

4.4

Varity_R

0.81

gMVP

0.87

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