dbSNP rs2070163: HCCS:p.Ala72Val (chrX-11114949-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005333.5(HCCS):c.215C>T(p.Ala72Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,206,536 control chromosomes in the GnomAD database, including 363 homozygotes. There are 10,190 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A72A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.019 ( 24 hom., 594 hem., cov: 24)

Exomes 𝑓: 0.028 ( 339 hom. 9596 hem. )

Consequence

HCCS
NM_005333.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0440

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026522577).

BP6

Variant X-11114949-C-T is Benign according to our data. Variant chrX-11114949-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0195 (2183/112037) while in subpopulation NFE AF = 0.0303 (1611/53163). AF 95% confidence interval is 0.0291. There are 24 homozygotes in GnomAd4. There are 594 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 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
HCCS	NM_005333.5	MANE Select	c.215C>T	p.Ala72Val	missense	Exon 3 of 7	NP_005324.3
HCCS	NM_001122608.3		c.215C>T	p.Ala72Val	missense	Exon 3 of 7	NP_001116080.1
HCCS	NM_001171991.3		c.215C>T	p.Ala72Val	missense	Exon 3 of 7	NP_001165462.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HCCS	ENST00000380762.5	TSL:1 MANE Select	c.215C>T	p.Ala72Val	missense	Exon 3 of 7	ENSP00000370139.4
HCCS	ENST00000380763.7	TSL:1	c.215C>T	p.Ala72Val	missense	Exon 3 of 7	ENSP00000370140.3
HCCS	ENST00000321143.8	TSL:2	c.215C>T	p.Ala72Val	missense	Exon 3 of 7	ENSP00000326579.4

Frequencies

GnomAD3 genomes

AF:

0.0195

AC:

2184

AN:

111985

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00390

Gnomad AMI

AF:

0.00731

Gnomad AMR

AF:

0.0194

Gnomad ASJ

AF:

0.0464

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00448

Gnomad FIN

AF:

0.0124

Gnomad MID

AF:

0.0126

Gnomad NFE

AF:

0.0303

Gnomad OTH

AF:

0.0192

GnomAD2 exomes

AF:

0.0192

AC:

3513

AN:

183228

AF XY:

0.0195

show subpopulations

Gnomad AFR exome

AF:

0.00296

Gnomad AMR exome

AF:

0.0110

Gnomad ASJ exome

AF:

0.0531

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.0154

Gnomad NFE exome

AF:

0.0282

Gnomad OTH exome

AF:

0.0212

GnomAD4 exome

AF:

0.0276

AC:

30181

AN:

1094499

Hom.:

339

Cov.:

AF XY:

0.0266

AC XY:

9596

AN XY:

360161

show subpopulations

African (AFR)

AF:

0.00395

AC:

104

AN:

26346

American (AMR)

AF:

0.0123

AC:

432

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.0510

AC:

988

AN:

19361

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30191

South Asian (SAS)

AF:

0.00781

AC:

422

AN:

54055

European-Finnish (FIN)

AF:

0.0165

AC:

669

AN:

40508

Middle Eastern (MID)

AF:

0.0151

AC:

AN:

4099

European-Non Finnish (NFE)

AF:

0.0314

AC:

26342

AN:

838749

Other (OTH)

AF:

0.0252

AC:

1160

AN:

45986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

908

1816

2723

3631

4539

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1036

2072

3108

4144

5180

<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:

0.0195

AC:

2183

AN:

112037

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

594

AN XY:

34241

show subpopulations

African (AFR)

AF:

0.00389

AC:

120

AN:

30845

American (AMR)

AF:

0.0194

AC:

206

AN:

10634

Ashkenazi Jewish (ASJ)

AF:

0.0464

AC:

123

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3572

South Asian (SAS)

AF:

0.00449

AC:

AN:

2670

European-Finnish (FIN)

AF:

0.0124

AC:

AN:

6071

Middle Eastern (MID)

AF:

0.00917

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.0303

AC:

1611

AN:

53163

Other (OTH)

AF:

0.0189

AC:

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

164

245

327

409

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0270

Hom.:

1312

Bravo

AF:

0.0191

TwinsUK

AF:

0.0299

AC:

111

ALSPAC

AF:

0.0325

AC:

ESP6500AA

AF:

0.00365

AC:

ESP6500EA

AF:

0.0321

AC:

216

ExAC

AF:

0.0184

AC:

2233

EpiCase

AF:

0.0302

EpiControl

AF:

0.0287

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.041

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.41

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0027

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.0

PhyloP100

0.044

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.69

REVEL

Benign

0.15

Sift

Benign

0.31

Sift4G

Benign

0.27

Polyphen

0.0090

Vest4

0.022

MPC

0.38

ClinPred

0.0061

GERP RS

-9.3

Varity_R

0.038

gMVP

0.19

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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