rs121917889

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

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 (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.39

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

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 11671.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.649C>T	p.Arg217Cys	missense_variant	Exon 7 of 7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.649C>T	p.Arg217Cys	missense_variant	Exon 7 of 7		NP_001116080.1
HCCS	NM_001171991.3	c.649C>T	p.Arg217Cys	missense_variant	Exon 7 of 7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.649C>T	p.Arg217Cys	missense_variant	Exon 7 of 7	1	NM_005333.5	ENSP00000370139.4
HCCS	ENST00000380763.7	c.649C>T	p.Arg217Cys	missense_variant	Exon 7 of 7	1		ENSP00000370140.3
HCCS	ENST00000321143.8	c.649C>T	p.Arg217Cys	missense_variant	Exon 7 of 7	2		ENSP00000326579.4
ARHGAP6	ENST00000657361.1	c.1733-1607G>A		intron_variant	Intron 12 of 13			ENSP00000499351.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Linear skin defects with multiple congenital anomalies 1 Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Nov 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

HCCS-related disorder Pathogenic:1

Feb 27, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HCCS c.649C>T variant is predicted to result in the amino acid substitution p.Arg217Cys. This variant has been reported as arising de novo in a female patient with microphthalmia with linear skin defects syndrome (Patient MS2 in Wimplinger et al. 2006. PubMed ID: 17033964). 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). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

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;D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;.;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.7	H;H;H
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-7.9	D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.83
MutPred		0.96		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.94
gMVP		1.0

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: rs121917889; hg19: chrX-11139772;