rs367601527

Variant names:

• chrX-11118620-C-T
• rs367601527
• NM_005333.5:c.521C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_005333.5(HCCS):​c.521C>T​(p.Ala174Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,204,899 control chromosomes in the GnomAD database, including 1 homozygotes. There are 47 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A174S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (1 hom., 9 hem., cov: 23)
  • Exomes 𝑓: 0.00014 (0 hom. 38 hem.)
• Consequence: HCCS NM_005333.5 missense, splice_region
• Scores: Splicing: ADA: 0.0001959
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.14
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03423792).
• BP6: Variant X-11118620-C-T is Benign according to our data. Variant chrX-11118620-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 95275.
• BS2: High Hemizygotes in GnomAd4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCCS	NM_005333.5	MANE Select	c.521C>T	p.Ala174Val	missense splice_region	Exon 5 of 7	NP_005324.3	P53701
	HCCS	NM_001122608.3		c.521C>T	p.Ala174Val	missense splice_region	Exon 5 of 7	NP_001116080.1	P53701
	HCCS	NM_001171991.3		c.521C>T	p.Ala174Val	missense splice_region	Exon 5 of 7	NP_001165462.1	P53701

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCCS	ENST00000380762.5	TSL:1 MANE Select	c.521C>T	p.Ala174Val	missense splice_region	Exon 5 of 7	ENSP00000370139.4	P53701
	HCCS	ENST00000380763.7	TSL:1	c.521C>T	p.Ala174Val	missense splice_region	Exon 5 of 7	ENSP00000370140.3	P53701
	HCCS	ENST00000321143.8	TSL:2	c.521C>T	p.Ala174Val	missense splice_region	Exon 5 of 7	ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes AF: 0.000312 AC: 35 AN: 112071 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000973

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: 0.0000939

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000872 AC: 16 AN: 183450 AF XY: 0.0000589

Gnomad AFR exome AF: 0.000836

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000610

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000138 AC: 151 AN: 1092828 Hom.: 0 Cov.: 28 AF XY: 0.000106 AC XY: 38 AN XY: 358442

African (AFR) AF: 0.000570 AC: 15 AN: 26297

American (AMR) AF: 0.00 AC: 0 AN: 35195

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19348

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 54025

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40497

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4127

European-Non Finnish (NFE) AF: 0.000143 AC: 120 AN: 837292

Other (OTH) AF: 0.000349 AC: 16 AN: 45889

GnomAD4 genome AF: 0.000312 AC: 35 AN: 112071 Hom.: 1 Cov.: 23 AF XY: 0.000263 AC XY: 9 AN XY: 34237

African (AFR) AF: 0.000973 AC: 30 AN: 30828

American (AMR) AF: 0.00 AC: 0 AN: 10585

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3601

South Asian (SAS) AF: 0.00 AC: 0 AN: 2699

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6030

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000939 AC: 5 AN: 53238

Other (OTH) AF: 0.00 AC: 0 AN: 1509

Alfa AF: 0.000211 Hom.: 6

Bravo AF: 0.000359

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Benign	0.42	T
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.1	L
PhyloP100		-1.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.20
Sift	Benign	0.21	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.13
MVP		0.61
MPC		0.38
ClinPred		0.018	T
GERP RS		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.61
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.020		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: rs367601527; hg19: chrX-11136740; COSMIC: COSV58239084; COSMIC: COSV58239084;