18-46084207-C-A

Position:

• chr18-46084207-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000398752.11(ATP5F1A):​c.*75G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,280,988 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0068 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (16 hom.)
• Consequence: ATP5F1A ENST00000398752.11 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.268

Genes affected

ATP5F1A (HGNC:823): (ATP synthase F1 subunit alpha) This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, using an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel consists of three main subunits (a, b, c). This gene encodes the alpha subunit of the catalytic core. Alternatively spliced transcript variants encoding the different isoforms have been identified. Pseudogenes of this gene are located on chromosomes 9, 2, and 16. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 18-46084207-C-A is Benign according to our data. Variant chr18-46084207-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1199822.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00681 (1037/152232) while in subpopulation AFR AF= 0.0234 (971/41564). AF 95% confidence interval is 0.0221. There are 7 homozygotes in gnomad4. There are 479 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP5F1A	NM_004046.6	c.*75G>T		3_prime_UTR_variant	12/12	ENST00000398752.11	NP_004037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP5F1A	ENST00000398752.11	c.*75G>T		3_prime_UTR_variant	12/12	1	NM_004046.6	ENSP00000381736	P1

Frequencies

GnomAD3 genomes AF: 0.00677 AC: 1030 AN: 152114 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000739 AC: 834 AN: 1128756 Hom.: 16 Cov.: 14 AF XY: 0.000647 AC XY: 371 AN XY: 573160

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.0000457

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000966

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00681 AC: 1037 AN: 152232 Hom.: 7 Cov.: 33 AF XY: 0.00644 AC XY: 479 AN XY: 74430

Gnomad4 AFR AF: 0.0234

Gnomad4 AMR AF: 0.00341

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000909 Hom.: 0

Bravo AF: 0.00771

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.0
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs15042; hg19: chr18-43664173;