rs144641429

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2S) has been classified as Benign.

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

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

linear skin defects with multiple congenital anomalies 1
Inheritance: XL Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
linear skin defects with multiple congenital anomalies
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

HCCS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

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 VariationId is 129217.

BS2

High Hemizygotes in GnomAd4 at 30 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005333.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HCCS	NM_005333.5	MANE Select	c.5G>A	p.Gly2Asp	missense	Exon 2 of 7	NP_005324.3	P53701
HCCS	NM_001122608.3		c.5G>A	p.Gly2Asp	missense	Exon 2 of 7	NP_001116080.1	P53701
HCCS	NM_001171991.3		c.5G>A	p.Gly2Asp	missense	Exon 2 of 7	NP_001165462.1	P53701

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HCCS	ENST00000380762.5	TSL:1 MANE Select	c.5G>A	p.Gly2Asp	missense	Exon 2 of 7	ENSP00000370139.4	P53701
HCCS	ENST00000380763.7	TSL:1	c.5G>A	p.Gly2Asp	missense	Exon 2 of 7	ENSP00000370140.3	P53701
HCCS	ENST00000321143.8	TSL:2	c.5G>A	p.Gly2Asp	missense	Exon 2 of 7	ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

128

AN:

112558

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00131

AC:

241

AN:

183368

AF XY:

0.00136

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 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

African (AFR)

AF:

0.000229

AC:

AN:

26242

American (AMR)

AF:

0.000199

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19331

East Asian (EAS)

AF:

0.00

AC:

AN:

30181

South Asian (SAS)

AF:

0.000908

AC:

AN:

53962

European-Finnish (FIN)

AF:

0.000247

AC:

AN:

40485

Middle Eastern (MID)

AF:

0.000728

AC:

AN:

4120

European-Non Finnish (NFE)

AF:

0.00265

AC:

2211

AN:

834879

Other (OTH)

AF:

0.00168

AC:

AN:

45832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

151

227

302

378

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

148

222

296

370

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00115

AC:

129

AN:

112612

Hom.:

Cov.:

AF XY:

0.000863

AC XY:

AN XY:

34770

show subpopulations

African (AFR)

AF:

0.000258

AC:

AN:

31008

American (AMR)

AF:

0.0000932

AC:

AN:

10728

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3593

South Asian (SAS)

AF:

0.000734

AC:

AN:

2723

European-Finnish (FIN)

AF:

0.000162

AC:

AN:

6183

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00220

AC:

117

AN:

53293

Other (OTH)

AF:

0.00

AC:

AN:

1536

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00166

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

HCCS-related disorder (1)

Inborn genetic diseases (1)

Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.45

M_CAP

Pathogenic

0.68

MetaRNN

Benign

0.049

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.4

PhyloP100

4.5

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.33

Sift

Uncertain

0.026

Sift4G

Uncertain

0.035

Polyphen

0.0010

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

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over