chrX-11112125-C-T

Variant names:

• chrX-11112125-C-T
• rs754603090
• NM_005333.5:c.65C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005333.5(HCCS):​c.65C>T​(p.Pro22Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000178 in 112,574 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37933078).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCCS	NM_005333.5	c.65C>T	p.Pro22Leu	missense_variant	Exon 2 of 7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.65C>T	p.Pro22Leu	missense_variant	Exon 2 of 7		NP_001116080.1
HCCS	NM_001171991.3	c.65C>T	p.Pro22Leu	missense_variant	Exon 2 of 7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.65C>T	p.Pro22Leu	missense_variant	Exon 2 of 7	1	NM_005333.5	ENSP00000370139.4
HCCS	ENST00000380763.7	c.65C>T	p.Pro22Leu	missense_variant	Exon 2 of 7	1		ENSP00000370140.3
HCCS	ENST00000321143.8	c.65C>T	p.Pro22Leu	missense_variant	Exon 2 of 7	2		ENSP00000326579.4

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112518 Hom.: 0 Cov.: 24 AF XY: 0.0000289 AC XY: 1 AN XY: 34646

Gnomad AFR AF: 0.0000647

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183396 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67836

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112574 Hom.: 0 Cov.: 24 AF XY: 0.0000288 AC XY: 1 AN XY: 34712

Gnomad4 AFR AF: 0.0000646

Gnomad4 AMR AF: 0.00

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: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HCCS protein function. This variant has not been reported in the literature in individuals affected with HCCS-related conditions. This variant is present in population databases (rs754603090, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 22 of the HCCS protein (p.Pro22Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;D;D
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	.;.;D
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.4	M;M;M
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Uncertain	0.47
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.17	B;B;B
Vest4		0.31
MutPred		0.25		Loss of catalytic residue at P21 (P = 0.0179);Loss of catalytic residue at P21 (P = 0.0179);Loss of catalytic residue at P21 (P = 0.0179);
MVP		0.73
MPC		1.1
ClinPred		0.94	D
GERP RS		4.2
Varity_R		0.59
gMVP		0.54

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: rs754603090; hg19: chrX-11130245;