X-11121636-C-A

Variant names:

• chrX-11121636-C-A
• NM_005333.5:c.633C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_005333.5(HCCS):​c.633C>A​(p.His211Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,707 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38

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 8 ACMG points.

• PM1: In a mutagenesis_site No effect on holocytochrome C synthase activity. (size 0) in uniprot entity CCHL_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCCS	NM_005333.5	c.633C>A	p.His211Gln	missense_variant	Exon 7 of 7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.633C>A	p.His211Gln	missense_variant	Exon 7 of 7		NP_001116080.1
HCCS	NM_001171991.3	c.633C>A	p.His211Gln	missense_variant	Exon 7 of 7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.633C>A	p.His211Gln	missense_variant	Exon 7 of 7	1	NM_005333.5	ENSP00000370139.4
HCCS	ENST00000380763.7	c.633C>A	p.His211Gln	missense_variant	Exon 7 of 7	1		ENSP00000370140.3
HCCS	ENST00000321143.8	c.633C>A	p.His211Gln	missense_variant	Exon 7 of 7	2		ENSP00000326579.4
ARHGAP6	ENST00000657361.1	c.1733-1591G>T		intron_variant	Intron 12 of 13			ENSP00000499351.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096707 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362117

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: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	4.4
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.95	D;D;D
FATHMM_MKL	Benign	0.26	N
LIST_S2	Pathogenic	1.0	.;.;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	4.0	H;H;H
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.9	D;D;D
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.88
MutPred		0.90		Loss of catalytic residue at D212 (P = 0.0613);Loss of catalytic residue at D212 (P = 0.0613);Loss of catalytic residue at D212 (P = 0.0613);
MVP		0.96
MPC		1.2
ClinPred		1.0	D
GERP RS		-3.3
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-11139756;