rs761659830

Positions:

• chrX-11112154-A-G
• chrX-11112154-A-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005333.5(HCCS):​c.94A>G​(p.Met32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,072,854 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000016 (0 hom. 9 hem.)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.480

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0335778).
• BS2: High Hemizygotes in GnomAdExome4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HCCS	NM_005333.5	c.94A>G	p.Met32Val	missense_variant	2/7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.94A>G	p.Met32Val	missense_variant	2/7		NP_001116080.1
HCCS	NM_001171991.3	c.94A>G	p.Met32Val	missense_variant	2/7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.94A>G	p.Met32Val	missense_variant	2/7	1	NM_005333.5	ENSP00000370139.4
HCCS	ENST00000380763.7	c.94A>G	p.Met32Val	missense_variant	2/7	1		ENSP00000370140.3
HCCS	ENST00000321143.8	c.94A>G	p.Met32Val	missense_variant	2/7	2		ENSP00000326579.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000710 AC: 13 AN: 183154 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67622

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000474

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 17 AN: 1072854 Hom.: 0 Cov.: 27 AF XY: 0.0000265 AC XY: 9 AN XY: 339884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000455

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.85
DEOGEN2	Benign	0.24	T;T;T
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.44	.;.;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	L;L;L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.41	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.15
MutPred		0.19		Gain of methylation at K33 (P = 0.0279);Gain of methylation at K33 (P = 0.0279);Gain of methylation at K33 (P = 0.0279);
MVP		0.30
MPC		0.39
ClinPred		0.011	T
GERP RS		-1.3
Varity_R		0.075
gMVP		0.23

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: rs761659830; hg19: chrX-11130274;