Genetic Variant COX7C:p.Cys42Tyr (chr5-86619402-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001867.3(COX7C):c.125G>A(p.Cys42Tyr) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

COX7C
NM_001867.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.592

Variant links:

Genes affected

COX7C (HGNC:2292): (cytochrome c oxidase subunit 7C) Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene encodes subunit VIIc, which shares 87% and 85% amino acid sequence identity with mouse and bovine COX VIIc, respectively, and is found in all tissues. A pseudogene COX7CP1 has been found on chromosome 13. [provided by RefSeq, Jul 2008]

COX7C links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15791318).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX7C	NM_001867.3 link	c.125G>A	p.Cys42Tyr	missense_variant	Exon 2 of 3	ENST00000247655.4	NP_001858.1	P15954

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COX7C	ENST00000247655.4 link	c.125G>A	p.Cys42Tyr	missense_variant	Exon 2 of 3	1	NM_001867.3	ENSP00000247655.3		P15954

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.84e-7

AC:

AN:

1461484

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727056

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5558

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111940

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.125G>A (p.C42Y) alteration is located in exon 2 (coding exon 2) of the COX7C gene. This alteration results from a G to A substitution at nucleotide position 125, causing the cysteine (C) at amino acid position 42 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.22

T;T;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.59

.;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.93

PhyloP100

0.59

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.051

Sift

Uncertain

0.019

D;D;D

Sift4G

Uncertain

0.014

D;D;D

Polyphen

0.20

B;B;.

Vest4

0.35

MutPred

0.34

Loss of catalytic residue at L43 (P = 0.0272);Loss of catalytic residue at L43 (P = 0.0272);Loss of catalytic residue at L43 (P = 0.0272);

MVP

0.043

MPC

0.94

ClinPred

0.87

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.31

gMVP

0.62

Mutation Taster

=79/21

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Loading publications...

5-86619402-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over