NM_005333.5:c.5G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_005333.5(HCCS):c.5G>A(p.Gly2Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00207 in 1,202,840 control chromosomes in the GnomAD database, including 4 homozygotes. There are 723 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., 30 hem., cov: 24)

Exomes 𝑓: 0.0022 ( 4 hom. 693 hem. )

Consequence

HCCS
NM_005333.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 4.54

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a lipid_moiety_binding_region N-myristoyl glycine (size 0) in uniprot entity CCHL_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.049010843).

BP6

Variant X-11112065-G-A is Benign according to our data. Variant chrX-11112065-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129217.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}. Variant chrX-11112065-G-A is described in Lovd as [Benign]. Variant chrX-11112065-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 30 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCCS	NM_005333.5 link	c.5G>A	p.Gly2Asp	missense_variant	Exon 2 of 7	ENST00000380762.5	NP_005324.3	P53701A0A024RBY9
HCCS	NM_001122608.3 link	c.5G>A	p.Gly2Asp	missense_variant	Exon 2 of 7		NP_001116080.1	P53701A0A024RBY9
HCCS	NM_001171991.3 link	c.5G>A	p.Gly2Asp	missense_variant	Exon 2 of 7		NP_001165462.1	P53701A0A024RBY9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HCCS	ENST00000380762.5 link	c.5G>A	p.Gly2Asp	missense_variant	Exon 2 of 7	1	NM_005333.5	ENSP00000370139.4	P53701
HCCS	ENST00000380763.7 link	c.5G>A	p.Gly2Asp	missense_variant	Exon 2 of 7	1		ENSP00000370140.3	P53701
HCCS	ENST00000321143.8 link	c.5G>A	p.Gly2Asp	missense_variant	Exon 2 of 7	2		ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

128

AN:

112558

Hom.:

Cov.:

AF XY:

0.000864

AC XY:

AN XY:

34706

show subpopulations

Gnomad AFR

AF:

0.000259

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000933

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000732

Gnomad FIN

AF:

0.000162

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00218

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00131

AC:

241

AN:

183368

Hom.:

AF XY:

0.00136

AC XY:

AN XY:

67800

show subpopulations

Gnomad AFR exome

AF:

0.000228

Gnomad AMR exome

AF:

0.000219

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000839

Gnomad FIN exome

AF:

0.000189

Gnomad NFE exome

AF:

0.00254

Gnomad OTH exome

AF:

0.00110

GnomAD4 exome

AF:

0.00217

AC:

2363

AN:

1090228

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

693

AN XY:

356168

show subpopulations

Gnomad4 AFR exome

AF:

0.000229

Gnomad4 AMR exome

AF:

0.000199

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000908

Gnomad4 FIN exome

AF:

0.000247

Gnomad4 NFE exome

AF:

0.00265

Gnomad4 OTH exome

AF:

0.00168

GnomAD4 genome

AF:

0.00115

AC:

129

AN:

112612

Hom.:

Cov.:

AF XY:

0.000863

AC XY:

AN XY:

34770

show subpopulations

Gnomad4 AFR

AF:

0.000258

Gnomad4 AMR

AF:

0.0000932

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000734

Gnomad4 FIN

AF:

0.000162

Gnomad4 NFE

AF:

0.00220

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00180

Hom.:

Bravo

AF:

0.00113

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00415

AC:

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00327

AC:

ExAC

AF:

0.00143

AC:

174

EpiCase

AF:

0.00196

EpiControl

AF:

0.00237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Nov 14, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

Dec 10, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 06, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

HCCS-related disorder

Benign:1

Aug 10, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Intellectual disability

Benign:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T;T

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.45

.;.;T

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.049

T;T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.33

Sift

Uncertain

0.026

D;D;D

Sift4G

Uncertain

0.035

D;D;D

Polyphen

0.0010

B;B;B

Vest4

0.39

MVP

0.80

MPC

1.3

ClinPred

0.050

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.51

gMVP

0.66

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