rs193929392

Positions:

• chrX-11118574-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005333.5(HCCS):​c.475G>A​(p.Glu159Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 22)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.36

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]

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCCS	NM_005333.5	c.475G>A	p.Glu159Lys	missense_variant	5/7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.475G>A	p.Glu159Lys	missense_variant	5/7		NP_001116080.1
HCCS	NM_001171991.3	c.475G>A	p.Glu159Lys	missense_variant	5/7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.475G>A	p.Glu159Lys	missense_variant	5/7	1	NM_005333.5	ENSP00000370139	P1
HCCS	ENST00000380763.7	c.475G>A	p.Glu159Lys	missense_variant	5/7	1		ENSP00000370140	P1
HCCS	ENST00000321143.8	c.475G>A	p.Glu159Lys	missense_variant	5/7	2		ENSP00000326579	P1
ARHGAP6	ENST00000657361.1	c.1784-215C>T		intron_variant				ENSP00000499351	A2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 22

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Linear skin defects with multiple congenital anomalies 1 Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	.;.;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.3	H;H;H
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	D;D;D
Vest4		0.95
MutPred		0.96		Gain of MoRF binding (P = 0.0014);Gain of MoRF binding (P = 0.0014);Gain of MoRF binding (P = 0.0014);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98
gMVP		1.0

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

Other links and lift over

dbSNP: rs193929392; hg19: chrX-11136694;