rs1413276234

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-11114933-C-A
• chrX-11114933-C-G
• chrX-11114933-C-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>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
• 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>A	p.Pro67Thr	missense	Exon 3 of 7	NP_005324.3
	HCCS	NM_001122608.3		c.199C>A	p.Pro67Thr	missense	Exon 3 of 7	NP_001116080.1
	HCCS	NM_001171991.3		c.199C>A	p.Pro67Thr	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>A	p.Pro67Thr	missense	Exon 3 of 7	ENSP00000370139.4
	HCCS	ENST00000380763.7	TSL:1	c.199C>A	p.Pro67Thr	missense	Exon 3 of 7	ENSP00000370140.3
	HCCS	ENST00000321143.8	TSL:2	c.199C>A	p.Pro67Thr	missense	Exon 3 of 7	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

African (AFR) AF: 0.00 AC: 0 AN: 26308

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19349

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.00 AC: 0 AN: 54025

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40525

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4089

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 836456

Other (OTH) AF: 0.0000218 AC: 1 AN: 45912

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Linear skin defects with multiple congenital anomalies 1 (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		6.8
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.030	D
Polyphen		0.97	D
Vest4		0.56
MutPred		0.87		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
Mutation Taster		=57/43	polymorphism

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; COSMIC: COSV58238791; COSMIC: COSV58238791;