Genetic Variant HCCS:p.Asn16Asp (chrX-11112106-A-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_005333.5(HCCS):c.46A>G(p.Asn16Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000405 in 1,209,001 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 17 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.000026 ( 0 hom. 14 hem. )

Consequence

HCCS
NM_005333.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.586

Publications

0 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020869493).

BP6

Variant X-11112106-A-G is Benign according to our data. Variant chrX-11112106-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2391787.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 3 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.46A>G	p.Asn16Asp	missense	Exon 2 of 7	NP_005324.3	P53701
HCCS	NM_001122608.3		c.46A>G	p.Asn16Asp	missense	Exon 2 of 7	NP_001116080.1	P53701
HCCS	NM_001171991.3		c.46A>G	p.Asn16Asp	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.46A>G	p.Asn16Asp	missense	Exon 2 of 7	ENSP00000370139.4	P53701
HCCS	ENST00000380763.7	TSL:1	c.46A>G	p.Asn16Asp	missense	Exon 2 of 7	ENSP00000370140.3	P53701
HCCS	ENST00000321143.8	TSL:2	c.46A>G	p.Asn16Asp	missense	Exon 2 of 7	ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes

AF:

0.000187

AC:

AN:

112488

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000647

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00159

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:

0.00132

GnomAD2 exomes

AF:

0.0000436

AC:

AN:

183419

AF XY:

0.0000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000146

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000255

AC:

AN:

1096457

Hom.:

Cov.:

AF XY:

0.0000387

AC XY:

AN XY:

361847

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26368

American (AMR)

AF:

0.000227

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19378

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40520

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.0000107

AC:

AN:

840518

Other (OTH)

AF:

0.000196

AC:

AN:

46032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000187

AC:

AN:

112544

Hom.:

Cov.:

AF XY:

0.0000864

AC XY:

AN XY:

34708

show subpopulations

African (AFR)

AF:

0.0000645

AC:

AN:

30993

American (AMR)

AF:

0.00159

AC:

AN:

10715

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3596

South Asian (SAS)

AF:

0.00

AC:

AN:

2730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6172

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53249

Other (OTH)

AF:

0.00130

AC:

AN:

1535

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.000487

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.4

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.23

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.47

M_CAP

Benign

0.040

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.85

PhyloP100

0.59

PrimateAI

Benign

0.35

PROVEAN

Benign

0.080

REVEL

Benign

0.10

Sift

Benign

0.72

Sift4G

Benign

0.63

Polyphen

0.0

Vest4

0.084

MVP

0.81

MPC

0.44

ClinPred

0.014

GERP RS

-0.26

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.082

gMVP

0.22

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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