X-11118547-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_005333.5(HCCS):c.448A>G(p.Ile150Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,184,523 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 65 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.00015 ( 0 hom. 62 hem. )

Consequence

HCCS
NM_005333.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 8.72

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:

ARHGAP6 (HGNC:676): (Rho GTPase activating protein 6) This gene encodes a member of the rhoGAP family of proteins which play a role in the regulation of actin polymerization at the plasma membrane during several cellular processes. This protein is thought to have two independent functions, one as a GTPase-activating protein with specificity for RhoA, and another as a cytoskeletal protein that promotes actin remodeling. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ARHGAP6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP6

Variant X-11118547-A-G is Benign according to our data. Variant chrX-11118547-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1740941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCCS	NM_005333.5 link	c.448A>G	p.Ile150Val	missense_variant	Exon 5 of 7	ENST00000380762.5	NP_005324.3	P53701A0A024RBY9
HCCS	NM_001122608.3 link	c.448A>G	p.Ile150Val	missense_variant	Exon 5 of 7		NP_001116080.1	P53701A0A024RBY9
HCCS	NM_001171991.3 link	c.448A>G	p.Ile150Val	missense_variant	Exon 5 of 7		NP_001165462.1	P53701A0A024RBY9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HCCS	ENST00000380762.5 link	c.448A>G	p.Ile150Val	missense_variant	Exon 5 of 7	1	NM_005333.5	ENSP00000370139.4	P53701
HCCS	ENST00000380763.7 link	c.448A>G	p.Ile150Val	missense_variant	Exon 5 of 7	1		ENSP00000370140.3	P53701
HCCS	ENST00000321143.8 link	c.448A>G	p.Ile150Val	missense_variant	Exon 5 of 7	2		ENSP00000326579.4	P53701
ARHGAP6	ENST00000657361.1 link	c.1784-188T>C		intron_variant	Intron 13 of 13			ENSP00000499351.1	B4DN07

Frequencies

GnomAD3 genomes

AF:

0.0000981

AC:

AN:

112145

Hom.:

Cov.:

AF XY:

0.0000875

AC XY:

AN XY:

34295

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000207

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183453

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67905

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000488

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000149

AC:

160

AN:

1072378

Hom.:

Cov.:

AF XY:

0.000183

AC XY:

AN XY:

339648

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000182

Gnomad4 OTH exome

AF:

0.000243

GnomAD4 genome

AF:

0.0000981

AC:

AN:

112145

Hom.:

Cov.:

AF XY:

0.0000875

AC XY:

AN XY:

34295

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000207

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Dec 10, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided

Benign:1

Apr 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.089

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;T;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;.;D

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.51

D;D;D

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

1.3

L;L;L

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.97

N;N;N

REVEL

Uncertain

0.46

Sift

Benign

0.23

T;T;T

Sift4G

Benign

0.31

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.42

MutPred

0.53

Gain of MoRF binding (P = 0.1235);Gain of MoRF binding (P = 0.1235);Gain of MoRF binding (P = 0.1235);

MVP

0.84

MPC

1.1

ClinPred

0.84

GERP RS

4.4

Varity_R

0.42

gMVP

0.74

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

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