X-11112154-A-T

Variant names:

• chrX-11112154-A-T
• rs761659830
• NM_005333.5:c.94A>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005333.5(HCCS):​c.94A>T​(p.Met32Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,072,854 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000028 (0 hom. 2 hem.)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056488484).
• BP6: Variant X-11112154-A-T is Benign according to our data. Variant chrX-11112154-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 435395.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HCCS	NM_005333.5	c.94A>T	p.Met32Leu	missense_variant	Exon 2 of 7	ENST00000380762.5	NP_005324.3
HCCS	NM_001122608.3	c.94A>T	p.Met32Leu	missense_variant	Exon 2 of 7		NP_001116080.1
HCCS	NM_001171991.3	c.94A>T	p.Met32Leu	missense_variant	Exon 2 of 7		NP_001165462.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HCCS	ENST00000380762.5	c.94A>T	p.Met32Leu	missense_variant	Exon 2 of 7	1	NM_005333.5	ENSP00000370139.4
HCCS	ENST00000380763.7	c.94A>T	p.Met32Leu	missense_variant	Exon 2 of 7	1		ENSP00000370140.3
HCCS	ENST00000321143.8	c.94A>T	p.Met32Leu	missense_variant	Exon 2 of 7	2		ENSP00000326579.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183154 Hom.: 0 AF XY: 0.0000296 AC XY: 2 AN XY: 67622

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000730

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: 0.00000280 AC: 3 AN: 1072854 Hom.: 0 Cov.: 27 AF XY: 0.00000588 AC XY: 2 AN XY: 339884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000853

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

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 03, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Benign	0.32	T;T;T
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.35	.;.;T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.056	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.4	L;L;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.59	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0060	B;B;B
Vest4		0.19
MutPred		0.19		Gain of methylation at K33 (P = 0.0374);Gain of methylation at K33 (P = 0.0374);Gain of methylation at K33 (P = 0.0374);
MVP		0.39
MPC		0.36
ClinPred		0.015	T
GERP RS		-1.3
Varity_R		0.11
gMVP		0.19

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;