X-11114933-C-G

Variant names:

• chrX-11114933-C-G
• rs1413276234
• NM_005333.5:c.199C>G

Variant summary

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

The NM_005333.5(HCCS):​c.199C>G​(p.Pro67Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000916 in 1,092,050 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: 9.2e-7 (0 hom. 0 hem.)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.79

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]

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, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCCS	NM_005333.5	c.199C>G	p.Pro67Ala	missense_variant	Exon 3 of 7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.199C>G	p.Pro67Ala	missense_variant	Exon 3 of 7		NP_001116080.1
HCCS	NM_001171991.3	c.199C>G	p.Pro67Ala	missense_variant	Exon 3 of 7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.199C>G	p.Pro67Ala	missense_variant	Exon 3 of 7	1	NM_005333.5	ENSP00000370139.4
HCCS	ENST00000380763.7	c.199C>G	p.Pro67Ala	missense_variant	Exon 3 of 7	1		ENSP00000370140.3
HCCS	ENST00000321143.8	c.199C>G	p.Pro67Ala	missense_variant	Exon 3 of 7	2		ENSP00000326579.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1092050 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 357610

Gnomad4 AFR exome AF: 0.0000380

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: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.90	D;D;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	.;.;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.5	H;H;H
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.53
MutPred		0.89		Loss of catalytic residue at P67 (P = 0.016);Loss of catalytic residue at P67 (P = 0.016);Loss of catalytic residue at P67 (P = 0.016);
MVP		0.83
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.65
gMVP		0.72

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: rs1413276234; hg19: chrX-11133053;