dbSNP rs794727278: HCCS:p.Met32Thr (chrX-11112155-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_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. 16/21 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.899

Publications

0 publications found

Variant links:

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

HCCS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.035538167).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HCCS	NM_005333.5	MANE Select	c.95T>C	p.Met32Thr	missense	Exon 2 of 7	NP_005324.3	P53701
HCCS	NM_001122608.3		c.95T>C	p.Met32Thr	missense	Exon 2 of 7	NP_001116080.1	P53701
HCCS	NM_001171991.3		c.95T>C	p.Met32Thr	missense	Exon 2 of 7	NP_001165462.1	P53701

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HCCS	ENST00000380762.5	TSL:1 MANE Select	c.95T>C	p.Met32Thr	missense	Exon 2 of 7	ENSP00000370139.4	P53701
HCCS	ENST00000380763.7	TSL:1	c.95T>C	p.Met32Thr	missense	Exon 2 of 7	ENSP00000370140.3	P53701
HCCS	ENST00000321143.8	TSL:2	c.95T>C	p.Met32Thr	missense	Exon 2 of 7	ENSP00000326579.4	P53701

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1074108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

341050

African (AFR)

AF:

0.00

AC:

AN:

25961

American (AMR)

AF:

0.00

AC:

AN:

35175

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19252

East Asian (EAS)

AF:

0.00

AC:

AN:

30124

South Asian (SAS)

AF:

0.00

AC:

AN:

53580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40485

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4084

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

820124

Other (OTH)

AF:

0.00

AC:

AN:

45323

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

2.9

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.23

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.36

M_CAP

Benign

0.019

MetaRNN

Benign

0.036

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.41

PhyloP100

-0.90

PrimateAI

Benign

0.34

PROVEAN

Benign

0.080

REVEL

Benign

0.23

Sift

Benign

0.57

Sift4G

Benign

0.57

Polyphen

0.0

Vest4

0.17

MutPred

0.11

Gain of methylation at K33 (P = 0.0334)

MVP

0.29

MPC

0.44

ClinPred

0.024

GERP RS

-4.8

Varity_R

0.056

gMVP

0.20

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over