X-77902650-C-A

Position:

• chrX-77902650-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001866.3(COX7B):​c.48C>A​(p.Ser16Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,207,750 control chromosomes in the GnomAD database, including 21 homozygotes. There are 504 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (13 hom., 220 hem., cov: 23)
  • Exomes 𝑓: 0.00097 (8 hom. 284 hem.)
• Consequence: COX7B NM_001866.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.18

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041023195).
• BP6: Variant X-77902650-C-A is Benign according to our data. Variant chrX-77902650-C-A is described in ClinVar as [Benign]. Clinvar id is 381408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00813 (913/112282) while in subpopulation AFR AF= 0.0283 (874/30924). AF 95% confidence interval is 0.0267. There are 13 homozygotes in gnomad4. There are 220 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COX7B	NM_001866.3	c.48C>A	p.Ser16Arg	missense_variant	2/3	ENST00000650309.2	NP_001857.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COX7B	ENST00000650309.2	c.48C>A	p.Ser16Arg	missense_variant	2/3		NM_001866.3	ENSP00000497474.1
COX7B	ENST00000475465.1	c.48C>A	p.Ser16Arg	missense_variant	2/2	2		ENSP00000497958.1
COX7B	ENST00000647835.1	c.41C>A	p.Ala14Glu	missense_variant, splice_region_variant	2/3			ENSP00000497517.1
COX7B	ENST00000373335	c.-13C>A		5_prime_UTR_variant	3/4	2		ENSP00000496880.1

Frequencies

GnomAD3 genomes AF: 0.00814 AC: 913 AN: 112229 Hom.: 13 Cov.: 23 AF XY: 0.00637 AC XY: 219 AN XY: 34397

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00246

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: 0.000131

Gnomad OTH AF: 0.00399

GnomAD3 exomes AF: 0.00255 AC: 465 AN: 182112 Hom.: 4 AF XY: 0.00169 AC XY: 113 AN XY: 66758

Gnomad AFR exome AF: 0.0283

Gnomad AMR exome AF: 0.00279

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: 0.000123

Gnomad OTH exome AF: 0.00156

GnomAD4 exome AF: 0.000970 AC: 1063 AN: 1095468 Hom.: 8 Cov.: 29 AF XY: 0.000785 AC XY: 284 AN XY: 361982

Gnomad4 AFR exome AF: 0.0299

Gnomad4 AMR exome AF: 0.00305

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000130

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000642

Gnomad4 OTH exome AF: 0.00220

GnomAD4 genome AF: 0.00813 AC: 913 AN: 112282 Hom.: 13 Cov.: 23 AF XY: 0.00638 AC XY: 220 AN XY: 34460

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.00246

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000131

Gnomad4 OTH AF: 0.00394

Alfa AF: 0.000950 Hom.: 35

Bravo AF: 0.00912

ESP6500AA AF: 0.0263 AC: 101

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00287 AC: 348

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 15, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	20
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.67	D
MetaRNN	Benign	0.0041	T
ClinPred		0.034	T
GERP RS		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs61752458; hg19: chrX-77158147;