chr21-25725268-C-T

Variant names:

• chr21-25725268-C-T
• NM_001003703.2:c.247G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.52

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5PF	NM_001003703.2	c.247G>A	p.Gly83Ser	missense_variant	Exon 3 of 4	ENST00000284971.8	NP_001003703.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP5PF	ENST00000284971.8	c.247G>A	p.Gly83Ser	missense_variant	Exon 3 of 4	1	NM_001003703.2	ENSP00000284971.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461004 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726820

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;T;.;T;T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.79	T;.;.;T;.;.;T
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.045	D
MutationAssessor	Uncertain	2.9	.;M;M;.;M;M;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D;D
REVEL	Uncertain	0.54
Sift	Benign	0.058	T;D;D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D;D;D
Polyphen		1.0	.;D;D;.;D;D;D
Vest4		0.82
MutPred		0.62		Gain of ubiquitination at K79 (P = 0.0619);Gain of ubiquitination at K79 (P = 0.0619);Gain of ubiquitination at K79 (P = 0.0619);.;Gain of ubiquitination at K79 (P = 0.0619);Gain of ubiquitination at K79 (P = 0.0619);Gain of ubiquitination at K79 (P = 0.0619);
MVP		0.72
MPC		0.60
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr21-27097579;