rs121917889

Variant names:

• chrX-11121652-C-T
• rs121917889
• NM_005333.5:c.649C>T
• HCCS p.Arg217Cys

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_005333.5(HCCS):​c.649C>T​(p.Arg217Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV004112583: Functional assays in this same paper found that the p.Arg217Cys substitution causes a decrease in protein activity (Wimplinger et al. 2006. PubMed ID: 17033964).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R217H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.39
• Publications: 12 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]

ARHGAP6 (HGNC:676): (Rho GTPase activating protein 6) This gene encodes a member of the rhoGAP family of proteins which play a role in the regulation of actin polymerization at the plasma membrane during several cellular processes. This protein is thought to have two independent functions, one as a GTPase-activating protein with specificity for RhoA, and another as a cytoskeletal protein that promotes actin remodeling. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004112583: Functional assays in this same paper found that the p.Arg217Cys substitution causes a decrease in protein activity (Wimplinger et al. 2006. PubMed ID: 17033964).
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-11121653-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3390917.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-11121652-C-T is Pathogenic according to our data. Variant chrX-11121652-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 11671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCCS	NM_005333.5	MANE Select	c.649C>T	p.Arg217Cys	missense	Exon 7 of 7	NP_005324.3	P53701
	HCCS	NM_001122608.3		c.649C>T	p.Arg217Cys	missense	Exon 7 of 7	NP_001116080.1	P53701
	HCCS	NM_001171991.3		c.649C>T	p.Arg217Cys	missense	Exon 7 of 7	NP_001165462.1	P53701

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCCS	ENST00000380762.5	TSL:1 MANE Select	c.649C>T	p.Arg217Cys	missense	Exon 7 of 7	ENSP00000370139.4	P53701
	HCCS	ENST00000380763.7	TSL:1	c.649C>T	p.Arg217Cys	missense	Exon 7 of 7	ENSP00000370140.3	P53701
	HCCS	ENST00000321143.8	TSL:2	c.649C>T	p.Arg217Cys	missense	Exon 7 of 7	ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

Alfa AF: 0.0000653 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	HCCS-related disorder (1)
1	-	-	Linear skin defects with multiple congenital anomalies 1 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.9	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.94
gMVP		1.0
Mutation Taster		=7/93	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs121917889;

hg19: chrX-11139772;