Genetic Variant ATPAF1:p.Pro56Thr (chr1-46668157-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001394565.1(ATPAF1):c.166C>A(p.Pro56Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000241 in 1,246,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. P56S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000024 ( 0 hom. )

Consequence

ATPAF1
NM_001394565.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.232

Publications

0 publications found

Variant links:

Genes affected

ATPAF1 (HGNC:18803): (ATP synthase mitochondrial F1 complex assembly factor 1) This gene encodes an assembly factor for the F(1) component of the mitochondrial ATP synthase. This protein binds specifically to the F1 beta subunit and is thought to prevent this subunit from forming nonproductive homooligomers during enzyme assembly. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Aug 2011]

ATPAF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0770559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATPAF1	NM_001394565.1 link	c.166C>A	p.Pro56Thr	missense_variant	Exon 1 of 9	ENST00000574428.6	NP_001381494.1
ATPAF1	NM_022745.6 link	c.235C>A	p.Pro79Thr	missense_variant	Exon 1 of 9		NP_073582.3	Q5TC12I3L448
ATPAF1	NM_001042546.2 link	c.235C>A	p.Pro79Thr	missense_variant	Exon 1 of 7		NP_001036011.2	Q5TC12A8MRA7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATPAF1	ENST00000574428.6 link	c.166C>A	p.Pro56Thr	missense_variant	Exon 1 of 9	1	NM_001394565.1	ENSP00000459167.2		Q5TC12-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000241

AC:

AN:

1246812

Hom.:

Cov.:

AF XY:

0.00000327

AC XY:

AN XY:

611492

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

24858

American (AMR)

AF:

0.0000623

AC:

AN:

16056

Ashkenazi Jewish (ASJ)

AF:

0.0000504

AC:

AN:

19852

East Asian (EAS)

AF:

0.00

AC:

AN:

27430

South Asian (SAS)

AF:

0.0000171

AC:

AN:

58572

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3596

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1009412

Other (OTH)

AF:

0.00

AC:

AN:

50784

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.242

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.0073

T;T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.63

.;T;T;T

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.077

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

.;.;N;.

PhyloP100

0.23

PrimateAI

Pathogenic

0.82

REVEL

Benign

0.061

Sift4G

Benign

0.096

T;T;T;T

Polyphen

0.0

.;.;B;.

Vest4

0.13

MutPred

0.091

.;.;Gain of phosphorylation at P56 (P = 0.0131);.;

MVP

0.061

MPC

0.51

ClinPred

0.046

GERP RS

-2.9

PromoterAI

0.020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.036

gMVP

0.43

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over