X-11120988-G-A

Variant names:

• chrX-11120988-G-A
• rs2045487420
• NM_005333.5:c.603G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005333.5(HCCS):​c.603G>A​(p.Trp201*) variant causes a stop gained 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 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.25

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.253 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-11120988-G-A is Pathogenic according to our data. Variant chrX-11120988-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3390916.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.603G>A	p.Trp201*	stop_gained	Exon 6 of 7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.603G>A	p.Trp201*	stop_gained	Exon 6 of 7		NP_001116080.1
HCCS	NM_001171991.3	c.603G>A	p.Trp201*	stop_gained	Exon 6 of 7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.603G>A	p.Trp201*	stop_gained	Exon 6 of 7	1	NM_005333.5	ENSP00000370139.4
HCCS	ENST00000380763.7	c.603G>A	p.Trp201*	stop_gained	Exon 6 of 7	1		ENSP00000370140.3
HCCS	ENST00000321143.8	c.603G>A	p.Trp201*	stop_gained	Exon 6 of 7	2		ENSP00000326579.4
ARHGAP6	ENST00000657361.1	c.1733-943C>T		intron_variant	Intron 12 of 13			ENSP00000499351.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Linear skin defects with multiple congenital anomalies 1 Pathogenic:1

Nov 12, 2024

Human Developmental Genetics Laboratory, Medical College of Wisconsin

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The NM_005333.5:c.603G>A generates a premature stop codon with the truncated transcript missing the final domain, important for folding and stability of the protein. Similar truncating alleles are reported in other individuals with MLS. The variant is absent in gnomAD v4.1.0. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.87
GERP RS		5.9

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: rs2045487420; hg19: chrX-11139108;