NM_001394565.1:c.166C>T

Variant names:

• chr1-46668157-G-A
• rs909032734
• NM_001394565.1:c.166C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394565.1(ATPAF1):​c.166C>T​(p.Pro56Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000016 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: ATPAF1 NM_001394565.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.232
• Publications: 0 publications found

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]

ACMG classification

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=0.075681776).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001394565.1. 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
	ATPAF1	NM_001394565.1	MANE Select	c.166C>T	p.Pro56Ser	missense	Exon 1 of 9	NP_001381494.1	Q5TC12-1
	ATPAF1	NM_022745.6		c.235C>T	p.Pro79Ser	missense	Exon 1 of 9	NP_073582.3	I3L448
	ATPAF1	NM_001042546.2		c.235C>T	p.Pro79Ser	missense	Exon 1 of 7	NP_001036011.2	Q5TC12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATPAF1	ENST00000574428.6	TSL:1 MANE Select	c.166C>T	p.Pro56Ser	missense	Exon 1 of 9	ENSP00000459167.2	Q5TC12-1
	ATPAF1	ENST00000576409.5	TSL:1	c.235C>T	p.Pro79Ser	missense	Exon 1 of 9	ENSP00000460964.1	I3L448
	ATPAF1	ENST00000870207.1		c.166C>T	p.Pro56Ser	missense	Exon 1 of 9	ENSP00000540266.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000160 AC: 2 AN: 1246812 Hom.: 0 Cov.: 35 AF XY: 0.00000164 AC XY: 1 AN XY: 611492

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

African (AFR) AF: 0.00 AC: 0 AN: 24858

American (AMR) AF: 0.00 AC: 0 AN: 16056

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19852

East Asian (EAS) AF: 0.00 AC: 0 AN: 27430

South Asian (SAS) AF: 0.00 AC: 0 AN: 58572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36252

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3596

European-Non Finnish (NFE) AF: 0.00000198 AC: 2 AN: 1009412

Other (OTH) AF: 0.00 AC: 0 AN: 50784

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
DANN	Benign	0.90
DEOGEN2	Benign	0.0087	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.55	D
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.23
PrimateAI	Pathogenic	0.81	D
REVEL	Benign	0.035
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.078		Gain of phosphorylation at P56 (P = 0.013)
MVP		0.067
MPC		0.46
ClinPred		0.042	T
GERP RS		-2.9
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.024
gMVP		0.40
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs909032734; hg19: chr1-47133829;