4-673345-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_007100.4(ATP5ME):c.148A>C(p.Lys50Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00025 in 1,613,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: ATP5ME NM_007100.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.51

Genes affected

ATP5ME (HGNC:846): (ATP synthase membrane subunit e) 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 seems to have nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene encodes the e subunit of the Fo complex. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Jun 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.011625439).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP5ME	NM_007100.4	c.148A>C	p.Lys50Gln	missense_variant	3/4	ENST00000304312.5
ATP5ME	NR_033743.2	n.122A>C		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP5ME	ENST00000304312.5	c.148A>C	p.Lys50Gln	missense_variant	3/4	1	NM_007100.4	P1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000394 AC: 99 AN: 251274 Hom.: 0 AF XY: 0.000419 AC XY: 57 AN XY: 135888

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000252 AC: 369 AN: 1461508 Hom.: 0 Cov.: 32 AF XY: 0.000249 AC XY: 181 AN XY: 727048

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00176

Gnomad4 EAS exome AF: 0.00121

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000170

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74496

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000399 Hom.: 0

Bravo AF: 0.000257

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000338 AC: 41

EpiCase AF: 0.000327

EpiControl AF: 0.000296

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

Mar 23, 2022

The c.148A>C (p.K50Q) alteration is located in exon 3 (coding exon 3) of the ATP5I gene. This alteration results from a A to C substitution at nucleotide position 148, causing the lysine (K) at amino acid position 50 to be replaced by a glutamine (Q). 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	Benign	0.071
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	18
Dann	Benign	0.90
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.061
Sift	Benign	0.24	T
Sift4G	Benign	0.30	T
Polyphen		0.0020	B
Vest4		0.20
MVP		0.39
MPC		0.025
ClinPred		0.016	T
GERP RS		-1.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Varity_R		0.27
gMVP		0.52

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: rs147287885; hg19: chr4-667134;