rs367601527

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_005333.5(HCCS):c.521C>T(p.Ala174Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,204,899 control chromosomes in the GnomAD database, including 1 homozygotes. There are 47 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A174S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00031 ( 1 hom., 9 hem., cov: 23)

Exomes 𝑓: 0.00014 ( 0 hom. 38 hem. )

Consequence

HCCS
NM_005333.5 missense, splice_region

Scores

Splicing: ADA: 0.0001959

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -1.14

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 was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03423792).

BP6

Variant X-11118620-C-T is Benign according to our data. Variant chrX-11118620-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 95275.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

BS2

High Hemizygotes in GnomAd4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCCS	NM_005333.5 link	c.521C>T	p.Ala174Val	missense_variant, splice_region_variant	Exon 5 of 7	ENST00000380762.5	NP_005324.3	P53701A0A024RBY9
HCCS	NM_001122608.3 link	c.521C>T	p.Ala174Val	missense_variant, splice_region_variant	Exon 5 of 7		NP_001116080.1	P53701A0A024RBY9
HCCS	NM_001171991.3 link	c.521C>T	p.Ala174Val	missense_variant, splice_region_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.521C>T	p.Ala174Val	missense_variant, splice_region_variant	Exon 5 of 7	1	NM_005333.5	ENSP00000370139.4	P53701
HCCS	ENST00000380763.7 link	c.521C>T	p.Ala174Val	missense_variant, splice_region_variant	Exon 5 of 7	1		ENSP00000370140.3	P53701
HCCS	ENST00000321143.8 link	c.521C>T	p.Ala174Val	missense_variant, splice_region_variant	Exon 5 of 7	2		ENSP00000326579.4	P53701
ARHGAP6	ENST00000657361.1 link	c.1784-261G>A		intron_variant	Intron 13 of 13			ENSP00000499351.1	B4DN07

Frequencies

GnomAD3 genomes

AF:

0.000312

AC:

AN:

112071

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000973

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:

0.0000939

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000872

AC:

AN:

183450

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.000836

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000610

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000138

AC:

151

AN:

1092828

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

358442

show subpopulations

Gnomad4 AFR exome

AF:

0.000570

AC:

AN:

26297

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

35195

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19348

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

30158

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

54025

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

40497

Gnomad4 NFE exome

AF:

0.000143

AC:

120

AN:

837292

Gnomad4 Remaining exome

AF:

0.000349

AC:

AN:

45889

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.000312

AC:

AN:

112071

Hom.:

Cov.:

AF XY:

0.000263

AC XY:

AN XY:

34237

show subpopulations

Gnomad4 AFR

AF:

0.000973

AC:

0.000973141

AN:

0.000973141

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000939

AC:

0.0000939179

AN:

0.0000939179

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome 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

Alfa

AF:

0.000211

Hom.:

Bravo

AF:

0.000359

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 24, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

HCCS-related disorder

Benign:1

May 25, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.42

T;T;T

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.80

.;.;T

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.034

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.1

L;L;L

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.0010

B;B;B

Vest4

0.13

MVP

0.61

MPC

0.38

ClinPred

0.018

GERP RS

0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.61

Mutation Taster

=96/4

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.16

SpliceAI score (max)

0.020

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