Genetic Variant COA4:p.Val41Ala (chr11-73873257-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016565.3(COA4):c.122T>C(p.Val41Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

COA4
NM_016565.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.68

Variant links:

Genes affected

COA4 (HGNC:24604): (cytochrome c oxidase assembly factor 4 homolog) Predicted to be involved in mitochondrial cytochrome c oxidase assembly. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

COA4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21542382).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COA4	NM_016565.3 link	c.122T>C	p.Val41Ala	missense_variant	Exon 2 of 2	ENST00000355693.5	NP_057649.2	Q9NYJ1-1A0A024R5J6
COA4	XM_017017883.2 link	c.149T>C	p.Val50Ala	missense_variant	Exon 2 of 2		XP_016873372.1	Q9NYJ1-2
COA4	XM_017017884.2 link	c.122T>C	p.Val41Ala	missense_variant	Exon 3 of 3		XP_016873373.1	Q9NYJ1-1A0A024R5J6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COA4	ENST00000355693.5 link	c.122T>C	p.Val41Ala	missense_variant	Exon 2 of 2	1	NM_016565.3	ENSP00000347919.4	Q9NYJ1-1
COA4	ENST00000541455.1 link	c.149T>C	p.Val50Ala	missense_variant	Exon 2 of 2	5		ENSP00000440756.1	Q9NYJ1-2
COA4	ENST00000537289.1 link	c.122T>C	p.Val41Ala	missense_variant	Exon 3 of 3	2		ENSP00000437772.1	Q9NYJ1-1
COA4	ENST00000545127.1 link	c.122T>C	p.Val41Ala	missense_variant	Exon 2 of 2	2		ENSP00000443795.1	Q9NYJ1-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

251464

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00107

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:

0.0000267

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000827

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.122T>C (p.V41A) alteration is located in exon 2 (coding exon 1) of the COA4 gene. This alteration results from a T to C substitution at nucleotide position 122, causing the valine (V) at amino acid position 41 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.73

.;.;T;T

M_CAP

Benign

0.082

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Uncertain

-0.13

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-3.1

D;D;D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0060

D;D;D;D

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

0.96

D;D;.;D

Vest4

0.58

MutPred

0.48

Loss of catalytic residue at V41 (P = 0.0366);Loss of catalytic residue at V41 (P = 0.0366);.;Loss of catalytic residue at V41 (P = 0.0366);

MVP

0.76

MPC

0.72

ClinPred

0.47

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.64

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

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