chrX-77902688-G-A

Position:

chrX-77902688-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001866.3(COX7B):c.86G>A(p.Arg29His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,207,183 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 5 hem. )

Consequence

COX7B
NM_001866.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.60

Variant links:

Genes affected

COX7B (HGNC:2291): (cytochrome c oxidase subunit 7B) 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 VIIb, which is highly similar to bovine COX VIIb protein and is found in all tissues. This gene may have several pseudogenes on chromosomes 1, 2, 20 and 22. [provided by RefSeq, Jun 2011]

COX7B links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.049800098).

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX7B	NM_001866.3 linkuse as main transcript	c.86G>A	p.Arg29His	missense_variant	2/3	ENST00000650309.2	NP_001857.1	P24311

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COX7B	ENST00000650309.2 linkuse as main transcript	c.86G>A	p.Arg29His	missense_variant	2/3		NM_001866.3	ENSP00000497474.1	P24311
COX7B	ENST00000373335.4 linkuse as main transcript	c.26G>A	p.Arg9His	missense_variant	3/4	2		ENSP00000496880.1	A0A3B3IRN8
COX7B	ENST00000475465.1 linkuse as main transcript	c.86G>A	p.Arg29His	missense_variant	2/2	2		ENSP00000497958.1	A0A3B3ITX0
COX7B	ENST00000647835.1 linkuse as main transcript	c.79G>A	p.Val27Ile	missense_variant	2/3			ENSP00000497517.1	A0A3B3ISY5

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112093

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34261

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000164

AC:

AN:

182789

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67337

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000110

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:

0.0000164

AC:

AN:

1095090

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

361430

show subpopulations

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:

0.0000741

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112093

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34261

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Linear skin defects with multiple congenital anomalies 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 23, 2020

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 29 of the COX7B protein (p.Arg29His). This variant is present in population databases (rs782685682, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with COX7B-related conditions. ClinVar contains an entry for this variant (Variation ID: 1029387). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.40

DEOGEN2

Benign

0.17

T;.;.;T

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.19

.;T;T;T

M_CAP

Benign

0.0086

MetaRNN

Benign

0.050

T;T;T;T

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.39

PROVEAN

Benign

0.74

N;.;.;.

REVEL

Benign

0.051

Sift

Benign

0.86

T;.;.;.

Sift4G

Benign

0.66

T;.;.;.

Polyphen

0.021

B;.;.;B

Vest4

0.26

MutPred

0.35

Gain of ubiquitination at K28 (P = 0.0311);.;Gain of ubiquitination at K28 (P = 0.0311);Gain of ubiquitination at K28 (P = 0.0311);

MVP

0.18

MPC

0.36

ClinPred

0.10

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.051

gMVP

0.13

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over