chrX-11112064-G-A

Variant names:

• chrX-11112064-G-A
• NM_005333.5:c.4G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_005333.5(HCCS):​c.4G>A​(p.Gly2Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000184 in 1,088,600 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.34
• 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]

HCCS Gene-Disease associations (from GenCC):

• linear skin defects with multiple congenital anomalies 1

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• linear skin defects with multiple congenital anomalies

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant X-11112064-G-A is Benign according to our data. Variant chrX-11112064-G-A is described in ClinVar as Benign. ClinVar VariationId is 2804780.Status of the report is criteria_provided_single_submitter, 1 stars.

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.4G>A	p.Gly2Ser	missense	Exon 2 of 7	NP_005324.3	P53701
	HCCS	NM_001122608.3		c.4G>A	p.Gly2Ser	missense	Exon 2 of 7	NP_001116080.1	P53701
	HCCS	NM_001171991.3		c.4G>A	p.Gly2Ser	missense	Exon 2 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.4G>A	p.Gly2Ser	missense	Exon 2 of 7	ENSP00000370139.4	P53701
	HCCS	ENST00000380763.7	TSL:1	c.4G>A	p.Gly2Ser	missense	Exon 2 of 7	ENSP00000370140.3	P53701
	HCCS	ENST00000321143.8	TSL:2	c.4G>A	p.Gly2Ser	missense	Exon 2 of 7	ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1088600 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 354736

African (AFR) AF: 0.00 AC: 0 AN: 26206

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19327

East Asian (EAS) AF: 0.00 AC: 0 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 53930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4113

European-Non Finnish (NFE) AF: 0.00000240 AC: 2 AN: 833367

Other (OTH) AF: 0.00 AC: 0 AN: 45792

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.3
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.022	D
Sift4G	Benign	0.20	T
Polyphen		0.19	B
Vest4		0.48
MutPred		0.22		Loss of catalytic residue at G2 (P = 0.0025)
MVP		0.89
MPC		1.0
ClinPred		0.95	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.33
gMVP		0.56
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chrX-11130184;