1-46668088-G-A

Position:

• chr1-46668088-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001394565.1(ATPAF1):​c.235C>T​(p.Arg79Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000614 in 1,302,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000061 (0 hom.)
• Consequence: ATPAF1 NM_001394565.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATPAF1	NM_001394565.1	c.235C>T	p.Arg79Cys	missense_variant	1/9	ENST00000574428.6	NP_001381494.1
ATPAF1	NM_022745.6	c.304C>T	p.Arg102Cys	missense_variant	1/9		NP_073582.3
ATPAF1	NM_001042546.2	c.304C>T	p.Arg102Cys	missense_variant	1/7		NP_001036011.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATPAF1	ENST00000574428.6	c.235C>T	p.Arg79Cys	missense_variant	1/9	1	NM_001394565.1	ENSP00000459167.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000614 AC: 8 AN: 1302054 Hom.: 0 Cov.: 29 AF XY: 0.00000312 AC XY: 2 AN XY: 641368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000147

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000677

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2024

The c.304C>T (p.R102C) alteration is located in exon 1 (coding exon 1) of the ATPAF1 gene. This alteration results from a C to T substitution at nucleotide position 304, causing the arginine (R) at amino acid position 102 to be replaced by a cysteine (C). 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	0.39
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.90	.;.;L;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.3	.;D;.;D
REVEL	Uncertain	0.34
Sift	Benign	0.048	.;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.28
MutPred		0.70		.;.;Loss of MoRF binding (P = 0.0079);.;
MVP		0.57
MPC		1.5
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.72
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs1378161854; hg19: chr1-47133760;