X-11114895-C-T

Position:

• chrX-11114895-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005333.5(HCCS):​c.161C>T​(p.Pro54Leu) variant causes a missense change. 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 Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.863

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCCS	NM_005333.5	c.161C>T	p.Pro54Leu	missense_variant	3/7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.161C>T	p.Pro54Leu	missense_variant	3/7		NP_001116080.1
HCCS	NM_001171991.3	c.161C>T	p.Pro54Leu	missense_variant	3/7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.161C>T	p.Pro54Leu	missense_variant	3/7	1	NM_005333.5	ENSP00000370139.4
HCCS	ENST00000380763.7	c.161C>T	p.Pro54Leu	missense_variant	3/7	1		ENSP00000370140.3
HCCS	ENST00000321143.8	c.161C>T	p.Pro54Leu	missense_variant	3/7	2		ENSP00000326579.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Jun 27, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	.;.;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Pathogenic	3.6	H;H;H
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.038	D;D;D
Polyphen		0.95	P;P;P
Vest4		0.71
MutPred		0.51		Loss of disorder (P = 0.0312);Loss of disorder (P = 0.0312);Loss of disorder (P = 0.0312);
MVP		0.87
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.59
gMVP		0.53

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: rs1555955059; hg19: chrX-11133015;