X-11114929-G-A

Variant names:

• chrX-11114929-G-A
• rs2045437506
• NM_005333.5:c.195G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_005333.5(HCCS):​c.195G>A​(p.Glu65Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000458 in 1,092,510 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 3 hem.)
• Consequence: HCCS NM_005333.5 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.254

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant X-11114929-G-A is Benign according to our data. Variant chrX-11114929-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3054798.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.254 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCCS	NM_005333.5	c.195G>A	p.Glu65Glu	synonymous_variant	Exon 3 of 7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.195G>A	p.Glu65Glu	synonymous_variant	Exon 3 of 7		NP_001116080.1
HCCS	NM_001171991.3	c.195G>A	p.Glu65Glu	synonymous_variant	Exon 3 of 7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.195G>A	p.Glu65Glu	synonymous_variant	Exon 3 of 7	1	NM_005333.5	ENSP00000370139.4
HCCS	ENST00000380763.7	c.195G>A	p.Glu65Glu	synonymous_variant	Exon 3 of 7	1		ENSP00000370140.3
HCCS	ENST00000321143.8	c.195G>A	p.Glu65Glu	synonymous_variant	Exon 3 of 7	2		ENSP00000326579.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000458 AC: 5 AN: 1092510 Hom.: 0 Cov.: 29 AF XY: 0.00000838 AC XY: 3 AN XY: 357984

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

HCCS-related disorder Benign:1

Apr 20, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.8
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2045437506; hg19: chrX-11133049;