18-46084207-C-A

Variant names:

• chr18-46084207-C-A
• rs15042
• NM_004046.6:c.*75G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004046.6(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 NM_004046.6 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

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5F1A	NM_004046.6	c.*75G>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000398752.11	NP_004037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP5F1A	ENST00000398752	c.*75G>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_004046.6	ENSP00000381736.5

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 AC: 660 AN: 25938

Gnomad4 AMR exome AF: 0.00117 AC: 43 AN: 36600

Gnomad4 ASJ exome AF: 0.0000457 AC: 1 AN: 21872

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 37924

Gnomad4 SAS exome AF: 0.0000966 AC: 7 AN: 72472

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 48824

Gnomad4 NFE exome AF: 0.0000360 AC: 30 AN: 832766

Gnomad4 Remaining exome AF: 0.00174 AC: 85 AN: 48944

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 AC: 0.0233616 AN: 0.0233616

Gnomad4 AMR AF: 0.00341 AC: 0.00340626 AN: 0.00340626

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000118 AC: 0.000117606 AN: 0.000117606

Gnomad4 OTH AF: 0.00284 AC: 0.0028436 AN: 0.0028436

Alfa AF: 0.00199 Hom.: 1

Bravo AF: 0.00771

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 24, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
Mutation Taster		=100/0	polymorphism

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;