X-11114933-C-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005333.5(HCCS):​c.199C>T​(p.Pro67Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P67T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.79
• Publications: 4 publications found

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]

HCCS Gene-Disease associations (from GenCC):

• linear skin defects with multiple congenital anomalies 1

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• linear skin defects with multiple congenital anomalies

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005333.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCCS	NM_005333.5	MANE Select	c.199C>T	p.Pro67Ser	missense	Exon 3 of 7	NP_005324.3
	HCCS	NM_001122608.3		c.199C>T	p.Pro67Ser	missense	Exon 3 of 7	NP_001116080.1
	HCCS	NM_001171991.3		c.199C>T	p.Pro67Ser	missense	Exon 3 of 7	NP_001165462.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCCS	ENST00000380762.5	TSL:1 MANE Select	c.199C>T	p.Pro67Ser	missense	Exon 3 of 7	ENSP00000370139.4
	HCCS	ENST00000380763.7	TSL:1	c.199C>T	p.Pro67Ser	missense	Exon 3 of 7	ENSP00000370140.3
	HCCS	ENST00000321143.8	TSL:2	c.199C>T	p.Pro67Ser	missense	Exon 3 of 7	ENSP00000326579.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.010	D
Polyphen		0.93	P
Vest4		0.56
MutPred		0.88		Gain of phosphorylation at P67 (P = 0.0618)
MVP		0.76
MPC		0.91
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.66
gMVP		0.80
Mutation Taster		=25/75	disease causing

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

Other links and lift over

dbSNP: rs1413276234; hg19: chrX-11133053;