rs2070163

Positions:

chrX-11114949-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 -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 [Likely_benign]. Clinvar id is 129215.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-11114949-C-T is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCCS	NM_005333.5 linkuse as main transcript	c.215C>T	p.Ala72Val	missense_variant	3/7	ENST00000380762.5	NP_005324.3	P53701A0A024RBY9
HCCS	NM_001122608.3 linkuse as main transcript	c.215C>T	p.Ala72Val	missense_variant	3/7		NP_001116080.1	P53701A0A024RBY9
HCCS	NM_001171991.3 linkuse as main transcript	c.215C>T	p.Ala72Val	missense_variant	3/7		NP_001165462.1	P53701A0A024RBY9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HCCS	ENST00000380762.5 linkuse as main transcript	c.215C>T	p.Ala72Val	missense_variant	3/7	1	NM_005333.5	ENSP00000370139.4	P53701
HCCS	ENST00000380763.7 linkuse as main transcript	c.215C>T	p.Ala72Val	missense_variant	3/7	1		ENSP00000370140.3	P53701
HCCS	ENST00000321143.8 linkuse as main transcript	c.215C>T	p.Ala72Val	missense_variant	3/7	2		ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes

AF:

0.0195

AC:

2184

AN:

111985

Hom.:

Cov.:

AF XY:

0.0174

AC XY:

594

AN XY:

34179

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

GnomAD3 exomes

AF:

0.0192

AC:

3513

AN:

183228

Hom.:

AF XY:

0.0195

AC XY:

1322

AN XY:

67694

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 SAS exome

AF:

0.00645

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

Gnomad4 AFR exome

AF:

0.00395

Gnomad4 AMR exome

AF:

0.0123

Gnomad4 ASJ exome

AF:

0.0510

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.00781

Gnomad4 FIN exome

AF:

0.0165

Gnomad4 NFE exome

AF:

0.0314

Gnomad4 OTH exome

AF:

0.0252

GnomAD4 genome

AF:

0.0195

AC:

2183

AN:

112037

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

594

AN XY:

34241

show subpopulations

Gnomad4 AFR

AF:

0.00389

Gnomad4 AMR

AF:

0.0194

Gnomad4 ASJ

AF:

0.0464

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00449

Gnomad4 FIN

AF:

0.0124

Gnomad4 NFE

AF:

0.0303

Gnomad4 OTH

AF:

0.0189

Alfa

AF:

0.0284

Hom.:

1290

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

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.041

DANN

Benign

0.86

DEOGEN2

Benign

0.41

T;T;T

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.46

.;.;T

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.0

M;M;M

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.69

N;N;N

REVEL

Benign

0.15

Sift

Benign

0.31

T;T;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.0090

B;B;B

Vest4

0.022

MPC

0.38

ClinPred

0.0061

GERP RS

-9.3

Varity_R

0.038

gMVP

0.19

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

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