Genetic Variant COX7A1:p.Lys44Asn (chr19-36151517-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001864.4(COX7A1):c.132G>C(p.Lys44Asn) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K44Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

COX7A1
NM_001864.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.275

Publications

0 publications found

Variant links:

Genes affected

COX7A1 (HGNC:2287): (cytochrome c oxidase subunit 7A1) 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 polypeptide 1 (muscle isoform) of subunit VIIa and the polypeptide 1 is present only in muscle tissues. Other polypeptides of subunit VIIa are present in both muscle and nonmuscle tissues, and are encoded by different genes. [provided by RefSeq, Jul 2008]

COX7A1 links:

ENSG00000294115 (HGNC:):

ENSG00000294115 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.926

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001864.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COX7A1	NM_001864.4	MANE Select	c.132G>C	p.Lys44Asn	missense	Exon 3 of 4	NP_001855.1	Q6FGI7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COX7A1	ENST00000292907.8	TSL:1 MANE Select	c.132G>C	p.Lys44Asn	missense	Exon 3 of 4	ENSP00000292907.3	P24310
COX7A1	ENST00000589154.1	TSL:5	c.105G>C	p.Lys35Asn	missense	Exon 3 of 4	ENSP00000468063.3	K7ER11
COX7A1	ENST00000437291.6	TSL:3	c.-37G>C		5_prime_UTR	Exon 3 of 4	ENSP00000475885.1	U3KQH8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.0047

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.78

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.93

MetaSVM

Benign

-0.76

PhyloP100

-0.28

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.0

REVEL

Uncertain

0.53

Sift

Uncertain

0.020

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.74

MutPred

0.85

Loss of methylation at K44 (P = 0.0099)

MVP

0.35

MPC

1.5

ClinPred

1.0

GERP RS

-4.4

Varity_R

0.64

gMVP

0.90

Mutation Taster

=68/32

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over