rs372832496

Variant names:

• chrX-11118627-A-G
• rs372832496
• NM_005333.5:c.521+7A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005333.5(HCCS):​c.521+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,202,803 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 43 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 4 hem., cov: 23)
  • Exomes 𝑓: 0.00011 (0 hom. 39 hem.)
• Consequence: HCCS NM_005333.5 splice_region, intron
• Scores: Splicing: ADA: 0.0003601
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.43
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant X-11118627-A-G is Benign according to our data. Variant chrX-11118627-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 4 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005333.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCCS	NM_005333.5	MANE Select	c.521+7A>G		splice_region intron	N/A	NP_005324.3
	HCCS	NM_001122608.3		c.521+7A>G		splice_region intron	N/A	NP_001116080.1
	HCCS	NM_001171991.3		c.521+7A>G		splice_region intron	N/A	NP_001165462.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCCS	ENST00000380762.5	TSL:1 MANE Select	c.521+7A>G		splice_region intron	N/A	ENSP00000370139.4
	HCCS	ENST00000380763.7	TSL:1	c.521+7A>G		splice_region intron	N/A	ENSP00000370140.3
	ARHGAP6	ENST00000657361.1		c.1784-268T>C		intron	N/A	ENSP00000499351.1

Frequencies

GnomAD3 genomes AF: 0.000107 AC: 12 AN: 112435 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000225

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000180 AC: 33 AN: 183436 AF XY: 0.000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000183

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000113 AC: 123 AN: 1090314 Hom.: 0 Cov.: 27 AF XY: 0.000110 AC XY: 39 AN XY: 355920

African (AFR) AF: 0.00 AC: 0 AN: 26243

American (AMR) AF: 0.000312 AC: 11 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19326

East Asian (EAS) AF: 0.00 AC: 0 AN: 30158

South Asian (SAS) AF: 0.000204 AC: 11 AN: 53966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40503

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4118

European-Non Finnish (NFE) AF: 0.000115 AC: 96 AN: 834985

Other (OTH) AF: 0.000109 AC: 5 AN: 45813

GnomAD4 genome AF: 0.000107 AC: 12 AN: 112489 Hom.: 0 Cov.: 23 AF XY: 0.000115 AC XY: 4 AN XY: 34637

African (AFR) AF: 0.00 AC: 0 AN: 31039

American (AMR) AF: 0.00 AC: 0 AN: 10639

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3598

South Asian (SAS) AF: 0.00 AC: 0 AN: 2718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6091

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000225 AC: 12 AN: 53313

Other (OTH) AF: 0.00 AC: 0 AN: 1528

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000147

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	HCCS-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.4
DANN	Benign	0.83
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00036
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs372832496; hg19: chrX-11136747;