X-11120991-G-C

Position:

• chrX-11120991-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005333.5(HCCS):​c.606G>C​(p.Met202Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: HCCS NM_005333.5 missense, splice_region
• Scores: Splicing: ADA: 0.05040
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCCS	NM_005333.5	c.606G>C	p.Met202Ile	missense_variant, splice_region_variant	6/7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.606G>C	p.Met202Ile	missense_variant, splice_region_variant	6/7		NP_001116080.1
HCCS	NM_001171991.3	c.606G>C	p.Met202Ile	missense_variant, splice_region_variant	6/7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.606G>C	p.Met202Ile	missense_variant, splice_region_variant	6/7	1	NM_005333.5	ENSP00000370139	P1
HCCS	ENST00000380763.7	c.606G>C	p.Met202Ile	missense_variant, splice_region_variant	6/7	1		ENSP00000370140	P1
HCCS	ENST00000321143.8	c.606G>C	p.Met202Ile	missense_variant, splice_region_variant	6/7	2		ENSP00000326579	P1
ARHGAP6	ENST00000657361.1	c.1733-946C>G		intron_variant				ENSP00000499351	A2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 202 of the HCCS protein (p.Met202Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HCCS-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.75	D;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;.;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.063	T;T;T
Sift4G	Uncertain	0.040	D;D;D
Polyphen		0.0020	B;B;B
Vest4		0.65
MutPred		0.62		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.86
MPC		0.45
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.75
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.050
dbscSNV1_RF	Benign	0.25
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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-11139111;