X-11120047-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005333.5(HCCS):c.522-860T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 323,350 control chromosomes in the GnomAD database, including 2 homozygotes. There are 183 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., 71 hem., cov: 23)
  • Exomes 𝑓: 0.0015 (1 hom. 112 hem.)
• Consequence: HCCS NM_005333.5 intron
• Scores: Splicing: ADA: 0.0002072
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.857

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant X-11120047-T-C is Benign according to our data. Variant chrX-11120047-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2659981.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 71 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCCS	NM_005333.5	c.522-860T>C		intron_variant		ENST00000380762.5
HCCS	NM_001122608.3	c.522-860T>C		intron_variant
HCCS	NM_001171991.3	c.522-860T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCCS	ENST00000380762.5	c.522-860T>C		intron_variant		1	NM_005333.5	P1
HCCS	ENST00000380763.7	c.522-860T>C		intron_variant		1		P1
ARHGAP6	ENST00000657361.1	c.1733-2A>G		splice_acceptor_variant				A2
HCCS	ENST00000321143.8	c.522-860T>C		intron_variant		2		P1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 184 AN: 112254 Hom.: 1 Cov.: 23 AF XY: 0.00206 AC XY: 71 AN XY: 34414

Gnomad AFR AF: 0.000324

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.00188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00736

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.00197

GnomAD3 exomes AF: 0.00114 AC: 95 AN: 83168 Hom.: 0 AF XY: 0.00103 AC XY: 27 AN XY: 26292

Gnomad AFR exome AF: 0.000449

Gnomad AMR exome AF: 0.000594

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00716

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.00267

GnomAD4 exome AF: 0.00152 AC: 320 AN: 211041 Hom.: 1 Cov.: 0 AF XY: 0.00138 AC XY: 112 AN XY: 81069

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000690

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000592

Gnomad4 FIN exome AF: 0.00667

Gnomad4 NFE exome AF: 0.00189

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00164 AC: 184 AN: 112309 Hom.: 1 Cov.: 23 AF XY: 0.00206 AC XY: 71 AN XY: 34479

Gnomad4 AFR AF: 0.000323

Gnomad4 AMR AF: 0.00188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00736

Gnomad4 NFE AF: 0.00197

Gnomad4 OTH AF: 0.00195

Alfa AF: 0.00154 Hom.: 18

Bravo AF: 0.00115

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

ARHGAP6: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
Cadd	Benign	15
Dann	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.0
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: rs755537648; hg19: chrX-11138167;