rs1800640

Variant names:

• chr18-46091434-T-C
• rs1800640
• NM_004046.6:c.309+248A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004046.6(ATP5F1A):​c.309+248A>G 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 152,032 control chromosomes in the GnomAD database, including 11,686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.39 (11686 hom., cov: 32)
• Consequence: ATP5F1A NM_004046.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.877
• Publications: 9 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 18-46091434-T-C is Benign according to our data. Variant chr18-46091434-T-C is described in ClinVar as Benign. ClinVar VariationId is 683323.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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+248A>G		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+248A>G		intron_variant	Intron 3 of 11	1	NM_004046.6	ENSP00000381736.5

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58617 AN: 151914 Hom.: 11680 Cov.: 32

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.0624

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.407

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

GnomAD4 genome AF: 0.386 AC: 58654 AN: 152032 Hom.: 11686 Cov.: 32 AF XY: 0.382 AC XY: 28360 AN XY: 74308

African (AFR) AF: 0.372 AC: 15423 AN: 41460

American (AMR) AF: 0.340 AC: 5191 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1614 AN: 3470

East Asian (EAS) AF: 0.0623 AC: 323 AN: 5184

South Asian (SAS) AF: 0.440 AC: 2124 AN: 4828

European-Finnish (FIN) AF: 0.361 AC: 3807 AN: 10546

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

European-Non Finnish (NFE) AF: 0.424 AC: 28792 AN: 67964

Other (OTH) AF: 0.405 AC: 857 AN: 2116

Alfa AF: 0.400 Hom.: 1672

Bravo AF: 0.377

Asia WGS AF: 0.256 AC: 895 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.5
DANN	Benign	0.79
PhyloP100		0.88
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: rs1800640; hg19: chr18-43671400;