X-77902709-A-G

Position:

chrX-77902709-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_001866.3(COX7B):c.107A>G(p.Lys36Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000539 in 1,206,850 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000056 ( 0 hom. 20 hem. )

Consequence

COX7B
NM_001866.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 5.62

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3264845).

BP6

Variant X-77902709-A-G is Benign according to our data. Variant chrX-77902709-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2660959.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Hemizygotes in GnomAdExome4 at 20 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX7B	NM_001866.3 linkuse as main transcript	c.107A>G	p.Lys36Arg	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.107A>G	p.Lys36Arg	missense_variant	2/3		NM_001866.3	ENSP00000497474.1	P24311
COX7B	ENST00000373335.4 linkuse as main transcript	c.47A>G	p.Lys16Arg	missense_variant	3/4	2		ENSP00000496880.1	A0A3B3IRN8
COX7B	ENST00000475465.1 linkuse as main transcript	c.107A>G	p.Lys36Arg	missense_variant	2/2	2		ENSP00000497958.1	A0A3B3ITX0
COX7B	ENST00000647835.1 linkuse as main transcript	c.100A>G	p.Asn34Asp	missense_variant	2/3			ENSP00000497517.1	A0A3B3ISY5

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112329

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34475

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:

0.0000750

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000328

AC:

AN:

182971

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

67475

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000734

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000557

AC:

AN:

1094521

Hom.:

Cov.:

AF XY:

0.0000555

AC XY:

AN XY:

360681

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000714

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000356

AC:

AN:

112329

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34475

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:

0.0000750

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 23, 2022	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with COX7B-related conditions. This variant is present in population databases (rs782304953, gnomAD 0.007%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 36 of the COX7B protein (p.Lys36Arg). -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	COX7B: BP4, BS2 -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 19, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.087

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

D;.;.;D

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.83

.;T;D;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.33

T;T;T;T

MetaSVM

Benign

-0.77

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.8

D;.;.;.

REVEL

Benign

0.25

Sift

Uncertain

0.026

D;.;.;.

Sift4G

Uncertain

0.048

D;.;.;.

Polyphen

0.47

P;.;.;P

Vest4

0.61

MVP

0.82

MPC

0.41

ClinPred

0.31

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.51

gMVP

0.65

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