Variant chrX-11112125-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005333.5(HCCS):c.65C>T(p.Pro22Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000178 in 112,574 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Consequence

HCCS
NM_005333.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.90

Variant links:

Genes affected

HCCS (HGNC:4837): (holocytochrome c synthase) The protein encoded by this gene is an enzyme that covalently links a heme group to the apoprotein of cytochrome c. Defects in this gene are a cause of microphthalmia syndromic type 7 (MCOPS7). Three transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jan 2010]

HCCS links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37933078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCCS	NM_005333.5 link	c.65C>T	p.Pro22Leu	missense_variant	2/7	ENST00000380762.5	NP_005324.3	P53701A0A024RBY9
HCCS	NM_001122608.3 link	c.65C>T	p.Pro22Leu	missense_variant	2/7		NP_001116080.1	P53701A0A024RBY9
HCCS	NM_001171991.3 link	c.65C>T	p.Pro22Leu	missense_variant	2/7		NP_001165462.1	P53701A0A024RBY9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HCCS	ENST00000380762.5 link	c.65C>T	p.Pro22Leu	missense_variant	2/7	1	NM_005333.5	ENSP00000370139.4	P53701
HCCS	ENST00000380763.7 link	c.65C>T	p.Pro22Leu	missense_variant	2/7	1		ENSP00000370140.3	P53701
HCCS	ENST00000321143.8 link	c.65C>T	p.Pro22Leu	missense_variant	2/7	2		ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112518

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34646

show subpopulations

Gnomad AFR

AF:

0.0000647

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000109

AC:

AN:

183396

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67836

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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

Cov.:

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112574

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34712

show subpopulations

Gnomad4 AFR

AF:

0.0000646

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 03, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HCCS protein function. This variant has not been reported in the literature in individuals affected with HCCS-related conditions. This variant is present in population databases (rs754603090, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 22 of the HCCS protein (p.Pro22Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.057

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D;D

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.93

.;.;D

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Uncertain

0.11

MutationAssessor

Pathogenic

3.4

M;M;M

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-5.0

D;D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

0.17

B;B;B

Vest4

0.31

MutPred

0.25

Loss of catalytic residue at P21 (P = 0.0179);Loss of catalytic residue at P21 (P = 0.0179);Loss of catalytic residue at P21 (P = 0.0179);

MVP

0.73

MPC

1.1

ClinPred

0.94

GERP RS

4.2

Varity_R

0.59

gMVP

0.54

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