X-11114902-C-A

Variant names:

• chrX-11114902-C-A
• rs754033072
• NM_005333.5:c.168C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005333.5(HCCS):​c.168C>A​(p.His56Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000916 in 1,091,734 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCCS	NM_005333.5	c.168C>A	p.His56Gln	missense_variant	Exon 3 of 7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.168C>A	p.His56Gln	missense_variant	Exon 3 of 7		NP_001116080.1
HCCS	NM_001171991.3	c.168C>A	p.His56Gln	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.168C>A	p.His56Gln	missense_variant	Exon 3 of 7	1	NM_005333.5	ENSP00000370139.4
HCCS	ENST00000380763.7	c.168C>A	p.His56Gln	missense_variant	Exon 3 of 7	1		ENSP00000370140.3
HCCS	ENST00000321143.8	c.168C>A	p.His56Gln	missense_variant	Exon 3 of 7	2		ENSP00000326579.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000545 AC: 1 AN: 183476 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.16e-7 AC: 1 AN: 1091734 Hom.: 0 Cov.: 29 AF XY: 0.00000280 AC XY: 1 AN XY: 357288

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: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 08, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.168C>A (p.H56Q) alteration is located in exon 3 (coding exon 2) of the HCCS gene. This alteration results from a C to A substitution at nucleotide position 168, causing the histidine (H) at amino acid position 56 to be replaced by a glutamine (Q). 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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T;T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.82	.;.;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Uncertain	-0.056	T
MutationAssessor	Pathogenic	3.5	H;H;H
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Uncertain	0.63
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.94	P;P;P
Vest4		0.35
MutPred		0.51		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.95
MPC		0.55
ClinPred		0.75	D
GERP RS		3.3
Varity_R		0.50
gMVP		0.46

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

Other links and lift over

dbSNP: rs754033072; hg19: chrX-11133022;