chrX-77899574-C-A

Position:

• chrX-77899574-C-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001866.3(COX7B):​c.21C>A​(p.Ser7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,097,618 control chromosomes in the GnomAD database, including 1 homozygotes. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000014 (1 hom. 8 hem.)
• Consequence: COX7B NM_001866.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.132

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07009724).
• BP6: Variant X-77899574-C-A is Benign according to our data. Variant chrX-77899574-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2881696.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAdExome4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX7B	NM_001866.3	c.21C>A	p.Ser7Arg	missense_variant	1/3	ENST00000650309.2	NP_001857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX7B	ENST00000650309.2	c.21C>A	p.Ser7Arg	missense_variant	1/3		NM_001866.3	ENSP00000497474.1
COX7B	ENST00000475465.1	c.21C>A	p.Ser7Arg	missense_variant	1/2	2		ENSP00000497958.1
COX7B	ENST00000647835.1	c.21C>A	p.Ser7Arg	missense_variant	1/3			ENSP00000497517.1
COX7B	ENST00000373335	c.-164C>A		5_prime_UTR_variant	1/4	2		ENSP00000496880.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000438 AC: 8 AN: 182610 Hom.: 0 AF XY: 0.0000596 AC XY: 4 AN XY: 67092

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: 0.000371

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 15 AN: 1097618 Hom.: 1 Cov.: 29 AF XY: 0.0000220 AC XY: 8 AN XY: 362984

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: 0.000222

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 17, 2023

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 7 of the COX7B protein (p.Ser7Arg). This variant is present in population databases (rs782218608, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with COX7B-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 20, 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	0.19
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.24	T;.;T;.
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.076	.;T;T;.
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.070	T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.57	N;.;.;.
REVEL	Benign	0.020
Sift	Benign	0.30	T;.;.;.
Sift4G	Benign	0.18	T;.;.;.
Polyphen		0.061	B;.;B;.
Vest4		0.066
MutPred		0.50		Gain of methylation at K6 (P = 0.04);Gain of methylation at K6 (P = 0.04);Gain of methylation at K6 (P = 0.04);Gain of methylation at K6 (P = 0.04);
MVP		0.15
MPC		0.36
ClinPred		0.17	T
GERP RS		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.59

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

LitVar

Other links and lift over

dbSNP: rs782218608; hg19: chrX-77155071;