chrX-11114912-G-A

Variant names:

• chrX-11114912-G-A
• rs746570741
• NM_005333.5:c.178G>A

Variant summary

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

The NM_005333.5(HCCS):​c.178G>A​(p.Ala60Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000055 in 1,090,777 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 1 hem.)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.61
• 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.

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.178G>A	p.Ala60Thr	missense	Exon 3 of 7	NP_005324.3	P53701
	HCCS	NM_001122608.3		c.178G>A	p.Ala60Thr	missense	Exon 3 of 7	NP_001116080.1	P53701
	HCCS	NM_001171991.3		c.178G>A	p.Ala60Thr	missense	Exon 3 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.178G>A	p.Ala60Thr	missense	Exon 3 of 7	ENSP00000370139.4	P53701
	HCCS	ENST00000380763.7	TSL:1	c.178G>A	p.Ala60Thr	missense	Exon 3 of 7	ENSP00000370140.3	P53701
	HCCS	ENST00000321143.8	TSL:2	c.178G>A	p.Ala60Thr	missense	Exon 3 of 7	ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183458 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000550 AC: 6 AN: 1090777 Hom.: 0 Cov.: 29 AF XY: 0.00000281 AC XY: 1 AN XY: 356391

African (AFR) AF: 0.00 AC: 0 AN: 26253

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19336

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30183

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 53970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4104

European-Non Finnish (NFE) AF: 0.00000479 AC: 4 AN: 835330

Other (OTH) AF: 0.00 AC: 0 AN: 45876

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.020	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.14	N
REVEL	Uncertain	0.46
Sift	Benign	0.19	T
Sift4G	Benign	0.51	T
Polyphen		0.99	D
Vest4		0.56
MutPred		0.41		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.89
MPC		0.46
ClinPred		0.54	D
GERP RS		5.1
Varity_R		0.31
gMVP		0.46
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs746570741; hg19: chrX-11133032;