X-11120998-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005333.5(HCCS):c.608+5G>C variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: HCCS NM_005333.5 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.62

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCCS	NM_005333.5	c.608+5G>C		splice_donor_5th_base_variant, intron_variant		ENST00000380762.5
HCCS	NM_001122608.3	c.608+5G>C		splice_donor_5th_base_variant, intron_variant
HCCS	NM_001171991.3	c.608+5G>C		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCCS	ENST00000380762.5	c.608+5G>C		splice_donor_5th_base_variant, intron_variant		1	NM_005333.5	P1
HCCS	ENST00000380763.7	c.608+5G>C		splice_donor_5th_base_variant, intron_variant		1		P1
HCCS	ENST00000321143.8	c.608+5G>C		splice_donor_5th_base_variant, intron_variant		2		P1
ARHGAP6	ENST00000657361.1	c.1733-953C>G		intron_variant				A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Linear skin defects with multiple congenital anomalies 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Goettingen

Jul 22, 2023

The c.608+5G>C variant of the HCCS-gene is not found in the gnomAD database. It probably leads to an alteration of the WT-donor site, most probably affecting splicing, as is predicted by various in silico splicing prediction programs (Human Splicing Finder, SpliceSiteFinder-like, MaxEntScan, NNSPLICE, GeneSplicer and SpliceAI). Loss of function variation within the HCCS gene is a known mechanism of disease. To our knowledge, this variant has not been reported in the literature before. ACMG criteria used for classification: PM2_supp, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
Cadd	Pathogenic	28
Dann	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.62		Position offset: 34
DS_DL_spliceai		0.89		Position offset: -5

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-11139118;