X-11112062-T-C

Variant names:

• chrX-11112062-T-C
• NM_005333.5:c.2T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Supporting PM2 PP5_Moderate

The NM_005333.5(HCCS):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000921 in 1,086,313 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. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: HCCS NM_005333.5 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.11

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 5 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 27 codons. Genomic position: 11112139. Lost 0.098 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-11112062-T-C is Pathogenic according to our data. Variant chrX-11112062-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3064959.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCCS	NM_005333.5	c.2T>C	p.Met1?	start_lost	Exon 2 of 7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.2T>C	p.Met1?	start_lost	Exon 2 of 7		NP_001116080.1
HCCS	NM_001171991.3	c.2T>C	p.Met1?	start_lost	Exon 2 of 7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.2T>C	p.Met1?	start_lost	Exon 2 of 7	1	NM_005333.5	ENSP00000370139.4
HCCS	ENST00000380763.7	c.2T>C	p.Met1?	start_lost	Exon 2 of 7	1		ENSP00000370140.3
HCCS	ENST00000321143.8	c.2T>C	p.Met1?	start_lost	Exon 2 of 7	2		ENSP00000326579.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.21e-7 AC: 1 AN: 1086313 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 352737

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Linear skin defects with multiple congenital anomalies 1 Pathogenic:1

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.37
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.35	T;T;T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	.;.;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Benign	-0.33	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.083	B;B;B
Vest4		0.94
MutPred		0.98		Gain of glycosylation at M1 (P = 0.0075);Gain of glycosylation at M1 (P = 0.0075);Gain of glycosylation at M1 (P = 0.0075);
MVP		0.99
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.89
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-11130182;