18-46091274-G-T

Variant names:

• chr18-46091274-G-T
• rs1800639
• NM_004046.6:c.309+408C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004046.6(ATP5F1A):​c.309+408C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 151,944 control chromosomes in the GnomAD database, including 11,682 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.39 (11682 hom., cov: 32)
• Consequence: ATP5F1A NM_004046.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.231
• Publications: 12 publications found

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]

ATP5F1A Gene-Disease associations (from GenCC):

• mitochondrial complex V (ATP synthase) deficiency, nuclear type 4A

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial complex V (ATP synthase) deficiency, nuclear type 4B

  Inheritance: AR Classification: STRONG Submitted by: G2P
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: Illumina
• mitochondrial proton-transporting ATP synthase complex deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• combined oxidative phosphorylation deficiency 22

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5F1A	NM_004046.6	c.309+408C>A		intron_variant	Intron 3 of 11	ENST00000398752.11	NP_004037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP5F1A	ENST00000398752.11	c.309+408C>A		intron_variant	Intron 3 of 11	1	NM_004046.6	ENSP00000381736.5

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58606 AN: 151826 Hom.: 11676 Cov.: 32

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.464

Gnomad EAS AF: 0.0620

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.409

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.386 AC: 58643 AN: 151944 Hom.: 11682 Cov.: 32 AF XY: 0.382 AC XY: 28353 AN XY: 74242

African (AFR) AF: 0.372 AC: 15423 AN: 41438

American (AMR) AF: 0.341 AC: 5195 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 1609 AN: 3464

East Asian (EAS) AF: 0.0620 AC: 321 AN: 5178

South Asian (SAS) AF: 0.440 AC: 2122 AN: 4822

European-Finnish (FIN) AF: 0.362 AC: 3810 AN: 10526

Middle Eastern (MID) AF: 0.527 AC: 155 AN: 294

European-Non Finnish (NFE) AF: 0.424 AC: 28782 AN: 67950

Other (OTH) AF: 0.406 AC: 858 AN: 2112

Alfa AF: 0.290 Hom.: 1047

Bravo AF: 0.377

Asia WGS AF: 0.257 AC: 898 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.20
DANN	Benign	0.73
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800639; hg19: chr18-43671240;