Genetic Variant ATPAF1:p.Ser31Arg (chr1-46668230-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001394565.1(ATPAF1):c.93C>A(p.Ser31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000082 in 1,219,124 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S31N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

ATPAF1
NM_001394565.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.847

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.35154456).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATPAF1	NM_001394565.1 link	c.93C>A	p.Ser31Arg	missense_variant	Exon 1 of 9	ENST00000574428.6	NP_001381494.1
ATPAF1	NM_022745.6 link	c.162C>A	p.Ser54Arg	missense_variant	Exon 1 of 9		NP_073582.3	Q5TC12I3L448
ATPAF1	NM_001042546.2 link	c.162C>A	p.Ser54Arg	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.93C>A	p.Ser31Arg	missense_variant	Exon 1 of 9	1	NM_001394565.1	ENSP00000459167.2		Q5TC12-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.20e-7

AC:

AN:

1219124

Hom.:

Cov.:

AF XY:

0.00000168

AC XY:

AN XY:

595270

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:

24700

American (AMR)

AF:

0.00

AC:

AN:

17772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19482

East Asian (EAS)

AF:

0.00

AC:

AN:

26250

South Asian (SAS)

AF:

0.00

AC:

AN:

54714

European-Finnish (FIN)

AF:

0.0000331

AC:

AN:

30216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3502

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

993066

Other (OTH)

AF:

0.00

AC:

AN:

49422

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 06, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.162C>A (p.S54R) alteration is located in exon 1 (coding exon 1) of the ATPAF1 gene. This alteration results from a C to A substitution at nucleotide position 162, causing the serine (S) at amino acid position 54 to be replaced by an arginine (R). 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

T;T;T;T

Eigen

Benign

-0.054

Eigen_PC

Benign

0.020

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.74

.;T;T;T

M_CAP

Pathogenic

0.89

MetaRNN

Benign

0.35

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

.;.;L;.

PhyloP100

0.85

PrimateAI

Pathogenic

0.95

REVEL

Benign

0.20

Sift4G

Benign

0.10

T;T;T;T

Polyphen

0.65

.;.;P;.

Vest4

0.35

MutPred

0.38

.;.;Loss of catalytic residue at S31 (P = 0.004);.;

MVP

0.45

MPC

0.53

ClinPred

0.92

GERP RS

3.2

PromoterAI

-0.043

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.48

gMVP

0.53

Mutation Taster

=86/14

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over