Genetic Variant NM_001394961.1:c.251G>C (chr12-57235576-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001394961.1(COXFA4L2):c.251G>C(p.Arg84Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,628 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R84Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

COXFA4L2
NM_001394961.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.23

Publications

0 publications found

Variant links:

Genes affected

COXFA4L2 (HGNC:29836): (NDUFA4 mitochondrial complex associated like 2) Predicted to be integral component of membrane. Predicted to be part of mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

COXFA4L2 links:

ENSG00000295078 (HGNC:):

ENSG00000295078 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394961.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COXFA4L2	NM_001394961.1	MANE Select	c.251G>C	p.Arg84Pro	missense	Exon 4 of 4	NP_001381890.1	Q9NRX3
COXFA4L2	NM_001394960.1		c.251G>C	p.Arg84Pro	missense	Exon 5 of 5	NP_001381889.1	Q9NRX3
COXFA4L2	NM_020142.4		c.251G>C	p.Arg84Pro	missense	Exon 5 of 5	NP_064527.1	Q9NRX3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NDUFA4L2	ENST00000554503.6	TSL:1 MANE Select	c.251G>C	p.Arg84Pro	missense	Exon 4 of 4	ENSP00000450664.1	Q9NRX3
NDUFA4L2	ENST00000393825.5	TSL:1	c.251G>C	p.Arg84Pro	missense	Exon 5 of 5	ENSP00000377411.1	Q9NRX3
NDUFA4L2	ENST00000909958.1		c.407G>C	p.Arg136Pro	missense	Exon 5 of 5	ENSP00000580017.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251372

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000547

AC:

AN:

1461628

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727118

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111956

Other (OTH)

AF:

0.0000166

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.095

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.56

MetaSVM

Uncertain

0.082

PhyloP100

6.2

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.37

Sift

Benign

0.12

Sift4G

Benign

0.19

Polyphen

1.0

Vest4

0.50

MutPred

0.47

Gain of catalytic residue at R84 (P = 0.0112)

MVP

0.92

MPC

0.21

ClinPred

0.98

GERP RS

4.5

Varity_R

0.51

gMVP

0.45

Mutation Taster

=73/27

polymorphism

(source)

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

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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