Variant X-11112106-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 -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 id is 2391787.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCCS	NM_005333.5 linkuse as main transcript	c.46A>G	p.Asn16Asp	missense_variant	2/7	ENST00000380762.5	NP_005324.3	P53701A0A024RBY9
HCCS	NM_001122608.3 linkuse as main transcript	c.46A>G	p.Asn16Asp	missense_variant	2/7		NP_001116080.1	P53701A0A024RBY9
HCCS	NM_001171991.3 linkuse as main transcript	c.46A>G	p.Asn16Asp	missense_variant	2/7		NP_001165462.1	P53701A0A024RBY9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
HCCS	ENST00000380762.5 linkuse as main transcript	c.46A>G	p.Asn16Asp	missense_variant	2/7	1	NM_005333.5	ENSP00000370139.4	P53701
HCCS	ENST00000380763.7 linkuse as main transcript	c.46A>G	p.Asn16Asp	missense_variant	2/7	1		ENSP00000370140.3	P53701
HCCS	ENST00000321143.8 linkuse as main transcript	c.46A>G	p.Asn16Asp	missense_variant	2/7	2		ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes

AF:

0.000187

AC:

AN:

112488

Hom.:

Cov.:

AF XY:

0.0000866

AC XY:

AN XY:

34642

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

GnomAD3 exomes

AF:

0.0000436

AC:

AN:

183419

Hom.:

AF XY:

0.0000737

AC XY:

AN XY:

67855

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000107

Gnomad4 OTH exome

AF:

0.000196

GnomAD4 genome

AF:

0.000187

AC:

AN:

112544

Hom.:

Cov.:

AF XY:

0.0000864

AC XY:

AN XY:

34708

show subpopulations

Gnomad4 AFR

AF:

0.0000645

Gnomad4 AMR

AF:

0.00159

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00130

Bravo

AF:

0.000487

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

This alteration is classified as likely 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

0.054

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.4

DANN

Benign

0.52

DEOGEN2

Benign

0.23

T;T;T

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.47

.;.;T

M_CAP

Benign

0.040

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.85

L;L;L

PrimateAI

Benign

0.35

PROVEAN

Benign

0.080

N;N;N

REVEL

Benign

0.10

Sift

Benign

0.72

T;T;T

Sift4G

Benign

0.63

T;T;T

Polyphen

0.0

B;B;B

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

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

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