X-11114950-G-C

Position:

• chrX-11114950-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005333.5(HCCS):​c.216G>C​(p.Ala72=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,206,815 control chromosomes in the GnomAD database, including 2 homozygotes. There are 495 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 0.0011 (0 hom., 28 hem., cov: 24)
  • Exomes 𝑓: 0.0013 (2 hom. 467 hem.)
• Consequence: HCCS NM_005333.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.329

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-11114950-G-C is Benign according to our data. Variant chrX-11114950-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 167163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-11114950-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.329 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCCS	NM_005333.5	c.216G>C	p.Ala72=	synonymous_variant	3/7	ENST00000380762.5
HCCS	NM_001122608.3	c.216G>C	p.Ala72=	synonymous_variant	3/7
HCCS	NM_001171991.3	c.216G>C	p.Ala72=	synonymous_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCCS	ENST00000380762.5	c.216G>C	p.Ala72=	synonymous_variant	3/7	1	NM_005333.5	P1
HCCS	ENST00000380763.7	c.216G>C	p.Ala72=	synonymous_variant	3/7	1		P1
HCCS	ENST00000321143.8	c.216G>C	p.Ala72=	synonymous_variant	3/7	2		P1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 120 AN: 112110 Hom.: 0 Cov.: 24 AF XY: 0.000817 AC XY: 28 AN XY: 34290

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000743

Gnomad FIN AF: 0.00491

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00154

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00127 AC: 233 AN: 183249 Hom.: 0 AF XY: 0.00123 AC XY: 83 AN XY: 67717

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.00433

Gnomad NFE exome AF: 0.00164

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.00134 AC: 1466 AN: 1094653 Hom.: 2 Cov.: 29 AF XY: 0.00130 AC XY: 467 AN XY: 360157

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.000114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.00346

Gnomad4 NFE exome AF: 0.00140

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00107 AC: 120 AN: 112162 Hom.: 0 Cov.: 24 AF XY: 0.000815 AC XY: 28 AN XY: 34352

Gnomad4 AFR AF: 0.000194

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000746

Gnomad4 FIN AF: 0.00491

Gnomad4 NFE AF: 0.00154

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000800 Hom.: 7

Bravo AF: 0.000684

EpiCase AF: 0.00142

EpiControl AF: 0.00142

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

- -

History of neurodevelopmental disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2013

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.55
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs144152239; hg19: chrX-11133070;