chrX-11114933-C-A

Position:

• chrX-11114933-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005333.5(HCCS):​c.199C>A​(p.Pro67Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,092,050 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter 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 Likely_pathogenic. Variant got 6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCCS	NM_005333.5	c.199C>A	p.Pro67Thr	missense_variant	3/7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.199C>A	p.Pro67Thr	missense_variant	3/7		NP_001116080.1
HCCS	NM_001171991.3	c.199C>A	p.Pro67Thr	missense_variant	3/7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.199C>A	p.Pro67Thr	missense_variant	3/7	1	NM_005333.5	ENSP00000370139.4
HCCS	ENST00000380763.7	c.199C>A	p.Pro67Thr	missense_variant	3/7	1		ENSP00000370140.3
HCCS	ENST00000321143.8	c.199C>A	p.Pro67Thr	missense_variant	3/7	2		ENSP00000326579.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000275 AC: 3 AN: 1092050 Hom.: 0 Cov.: 29 AF XY: 0.00000280 AC XY: 1 AN XY: 357610

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: 0.0000218

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Linear skin defects with multiple congenital anomalies 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

May 03, 2020

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	.;.;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.3	M;M;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.030	D;D;D
Polyphen		0.97	D;D;D
Vest4		0.56
MutPred		0.87		Loss of catalytic residue at P67 (P = 0.0419);Loss of catalytic residue at P67 (P = 0.0419);Loss of catalytic residue at P67 (P = 0.0419);
MVP		0.82
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.82
gMVP		0.80

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: rs1413276234; hg19: chrX-11133053; COSMIC: COSV58238791; COSMIC: COSV58238791;