X-11112155-T-C

Position:

• chrX-11112155-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005333.5(HCCS):​c.95T>C​(p.Met32Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M32L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.899

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035538167).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HCCS	NM_005333.5	c.95T>C	p.Met32Thr	missense_variant	2/7	ENST00000380762.5
HCCS	NM_001122608.3	c.95T>C	p.Met32Thr	missense_variant	2/7
HCCS	NM_001171991.3	c.95T>C	p.Met32Thr	missense_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HCCS	ENST00000380762.5	c.95T>C	p.Met32Thr	missense_variant	2/7	1	NM_005333.5	P1
HCCS	ENST00000380763.7	c.95T>C	p.Met32Thr	missense_variant	2/7	1		P1
HCCS	ENST00000321143.8	c.95T>C	p.Met32Thr	missense_variant	2/7	2		P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1074108 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 341050

Gnomad4 AFR exome AF: 0.00

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.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 06, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.9
DANN	Benign	0.72
DEOGEN2	Benign	0.23	T;T;T
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.36	.;.;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.036	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.41	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.080	N;N;N
REVEL	Benign	0.23
Sift	Benign	0.57	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.17
MutPred		0.11		Gain of methylation at K33 (P = 0.0334);Gain of methylation at K33 (P = 0.0334);Gain of methylation at K33 (P = 0.0334);
MVP		0.29
MPC		0.44
ClinPred		0.024	T
GERP RS		-4.8
Varity_R		0.056
gMVP		0.20

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: rs794727278; hg19: chrX-11130275;