rs761659830

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 0.000016 (0 hom. 9 hem.)
• Consequence: HCCS NM_005333.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.480
• 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: Benign. The variant received -8 ACMG points.

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

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.94A>G	p.Met32Val	missense	Exon 2 of 7	NP_005324.3
	HCCS	NM_001122608.3		c.94A>G	p.Met32Val	missense	Exon 2 of 7	NP_001116080.1
	HCCS	NM_001171991.3		c.94A>G	p.Met32Val	missense	Exon 2 of 7	NP_001165462.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HCCS	ENST00000380762.5	TSL:1 MANE Select	c.94A>G	p.Met32Val	missense	Exon 2 of 7	ENSP00000370139.4
	HCCS	ENST00000380763.7	TSL:1	c.94A>G	p.Met32Val	missense	Exon 2 of 7	ENSP00000370140.3
	HCCS	ENST00000321143.8	TSL:2	c.94A>G	p.Met32Val	missense	Exon 2 of 7	ENSP00000326579.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000710 AC: 13 AN: 183154 AF XY: 0.000118

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 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

African (AFR) AF: 0.00 AC: 0 AN: 25930

American (AMR) AF: 0.000455 AC: 16 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19245

East Asian (EAS) AF: 0.00 AC: 0 AN: 30126

South Asian (SAS) AF: 0.0000187 AC: 1 AN: 53561

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40485

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4078

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 818976

Other (OTH) AF: 0.00 AC: 0 AN: 45280

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 v4.9

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
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.48
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.13
Sift	Benign	0.29	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.19		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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs761659830; hg19: chrX-11130274;