Genetic Variant ATP5PF:p.Gly83Ser (chr21-25725268-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001003703.2(ATP5PF):c.247G>A(p.Gly83Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,004 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. G83R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ATP5PF
NM_001003703.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.52

Publications

0 publications found

Variant links:

Genes affected

ATP5PF (HGNC:847): (ATP synthase peripheral stalk subunit F6) Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. It is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, which comprises the proton channel. The F1 complex consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled in a ratio of 3 alpha, 3 beta, and a single representative of the other 3. The Fo complex has nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene encodes the F6 subunit of the Fo complex. The F6 subunit is required for F1 and Fo interactions. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. This gene has 1 or more pseudogenes. [provided by RefSeq, Feb 2016]

ATP5PF links:

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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;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.832

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001003703.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP5PF	NM_001003703.2	MANE Select	c.247G>A	p.Gly83Ser	missense	Exon 3 of 4	NP_001003703.1	P18859-1
ATP5PF	NM_001003701.2		c.271G>A	p.Gly91Ser	missense	Exon 3 of 4	NP_001003701.1	P18859-2
ATP5PF	NM_001003696.2		c.247G>A	p.Gly83Ser	missense	Exon 3 of 4	NP_001003696.1	P18859-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATP5PF	ENST00000284971.8	TSL:1 MANE Select	c.247G>A	p.Gly83Ser	missense	Exon 3 of 4	ENSP00000284971.3	P18859-1
ATP5PF	ENST00000400093.3	TSL:1	c.247G>A	p.Gly83Ser	missense	Exon 3 of 4	ENSP00000382965.3	P18859-1
ATP5PF	ENST00000400099.5	TSL:5	c.247G>A	p.Gly83Ser	missense	Exon 3 of 5	ENSP00000382971.1	A8MUH2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461004

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726820

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5606

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111890

Other (OTH)

AF:

0.00

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.79

M_CAP

Benign

0.062

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.045

MutationAssessor

Uncertain

2.9

PhyloP100

6.5

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.54

Sift

Benign

0.058

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.82

MutPred

0.62

Gain of ubiquitination at K79 (P = 0.0619)

MVP

0.72

MPC

0.60

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.58

Mutation Taster

=14/86

disease causing

(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