Variant X-11120954-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005333.5(HCCS):c.569A>G(p.Lys190Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000179 in 112,031 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Consequence

HCCS
NM_005333.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.58

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21534795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
HCCS	NM_005333.5 linkuse as main transcript	c.569A>G	p.Lys190Arg	missense_variant	6/7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3 linkuse as main transcript	c.569A>G	p.Lys190Arg	missense_variant	6/7		NP_001116080.1
HCCS	NM_001171991.3 linkuse as main transcript	c.569A>G	p.Lys190Arg	missense_variant	6/7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
HCCS	ENST00000380762.5 linkuse as main transcript	c.569A>G	p.Lys190Arg	missense_variant	6/7	1	NM_005333.5	ENSP00000370139	P1
HCCS	ENST00000380763.7 linkuse as main transcript	c.569A>G	p.Lys190Arg	missense_variant	6/7	1		ENSP00000370140	P1
HCCS	ENST00000321143.8 linkuse as main transcript	c.569A>G	p.Lys190Arg	missense_variant	6/7	2		ENSP00000326579	P1
ARHGAP6	ENST00000657361.1 linkuse as main transcript	c.1733-909T>C		intron_variant				ENSP00000499351	A2

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

112031

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34233

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000188

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:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000179

AC:

AN:

112031

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34233

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000188

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:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.569A>G (p.K190R) alteration is located in exon 6 (coding exon 5) of the HCCS gene. This alteration results from a A to G substitution at nucleotide position 569, causing the lysine (K) at amino acid position 190 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;T;T

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.81

.;.;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.22

T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.0

M;M;M

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.025

B;B;B

Vest4

0.32

MutPred

0.49

Loss of ubiquitination at K190 (P = 0.0412);Loss of ubiquitination at K190 (P = 0.0412);Loss of ubiquitination at K190 (P = 0.0412);

MVP

0.76

MPC

0.35

ClinPred

0.35

GERP RS

1.8

Varity_R

0.21

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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