X-11118619-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005333.5(HCCS):c.520G>T(p.Ala174Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A174V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: HCCS NM_005333.5 missense, splice_region
• Scores: Splicing: ADA: 0.00006889
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.21

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037530184).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCCS	NM_005333.5	c.520G>T	p.Ala174Ser	missense_variant, splice_region_variant	5/7	ENST00000380762.5
HCCS	NM_001122608.3	c.520G>T	p.Ala174Ser	missense_variant, splice_region_variant	5/7
HCCS	NM_001171991.3	c.520G>T	p.Ala174Ser	missense_variant, splice_region_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCCS	ENST00000380762.5	c.520G>T	p.Ala174Ser	missense_variant, splice_region_variant	5/7	1	NM_005333.5	P1
HCCS	ENST00000380763.7	c.520G>T	p.Ala174Ser	missense_variant, splice_region_variant	5/7	1		P1
HCCS	ENST00000321143.8	c.520G>T	p.Ala174Ser	missense_variant, splice_region_variant	5/7	2		P1
ARHGAP6	ENST00000657361.1	c.1784-260C>A		intron_variant				A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

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

Revvity Omics, Revvity

Jul 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	7.9
Dann	Benign	0.88
DEOGEN2	Benign	0.22	T;T;T
FATHMM_MKL	Benign	0.091	N
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.81	L;L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.66	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.61	T;T;T
Sift4G	Benign	0.76	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.14
MutPred		0.31		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);
MVP		0.36
MPC		0.35
ClinPred		0.035	T
GERP RS		-6.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.11
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000069
dbscSNV1_RF	Benign	0.046
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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-11136739;