Genetic Variant COA5:p.Ala53Pro (chr2-98604134-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP5

The NM_001008215.3(COA5):c.157G>C(p.Ala53Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,318 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A53T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

COA5
NM_001008215.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.952

Publications

11 publications found

Variant links:

Genes affected

COA5 (HGNC:33848): (cytochrome c oxidase assembly factor 5) This gene encodes an ortholog of yeast Pet191, which in yeast is a subunit of a large oligomeric complex associated with the mitochondrial inner membrane, and required for the assembly of the cytochrome c oxidase complex. Mutations in this gene are associated with mitochondrial complex IV deficiency, a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to a severe disease affecting several tissues and organs. [provided by RefSeq, Dec 2011]

COA5 Gene-Disease associations (from GenCC):

cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

COA5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-98604134-C-G is Pathogenic according to our data. Variant chr2-98604134-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 31087.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008215.3. 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
	COA5	NM_001008215.3	MANE Select	c.157G>C	p.Ala53Pro	missense	Exon 2 of 3	NP_001008216.1	Q86WW8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COA5	ENST00000328709.8	TSL:1 MANE Select	c.157G>C	p.Ala53Pro	missense	Exon 2 of 3	ENSP00000330730.3	Q86WW8
COA5	ENST00000917724.1		c.199G>C	p.Ala67Pro	missense	Exon 3 of 4	ENSP00000587783.1
COA5	ENST00000409997.1	TSL:4	c.157G>C	p.Ala53Pro	missense	Exon 2 of 3	ENSP00000386934.1	B9A057

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461318

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727004

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111636

Other (OTH)

AF:

0.00

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.18

MetaRNN

Uncertain

0.68

MetaSVM

Benign

-0.52

PhyloP100

0.95

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.58

Sift

Benign

0.079

Sift4G

Uncertain

0.019

Polyphen

0.96

Vest4

0.46

MutPred

0.62

Gain of disorder (P = 0.0447)

MVP

0.53

MPC

0.28

ClinPred

0.73

GERP RS

3.0

Varity_R

0.80

gMVP

0.84

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over