chr18-46080434-C-A

Variant names:

• chr18-46080434-C-A
• rs3745004
• NM_004046.6:c.*3848G>T

Variant summary

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

The NM_004046.6(ATP5F1A):​c.*3848G>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 0.109 in 152,154 control chromosomes in the GnomAD database, including 1,044 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 0.11 (1044 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATP5F1A NM_004046.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0940
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP5F1A	NM_004046.6	c.*3848G>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	ENST00000398752.11	c.*3848G>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_004046.6	ENSP00000381736.5

Frequencies

GnomAD3 genomes AF: 0.109 AC: 16527 AN: 152036 Hom.: 1043 Cov.: 32

Gnomad AFR AF: 0.0610

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.0870

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.143

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.114

Gnomad OTH AF: 0.110

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.109 AC: 16528 AN: 152154 Hom.: 1044 Cov.: 32 AF XY: 0.111 AC XY: 8257 AN XY: 74392

African (AFR) AF: 0.0609 AC: 2530 AN: 41534

American (AMR) AF: 0.179 AC: 2737 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 349 AN: 3464

East Asian (EAS) AF: 0.0872 AC: 451 AN: 5172

South Asian (SAS) AF: 0.166 AC: 801 AN: 4826

European-Finnish (FIN) AF: 0.143 AC: 1512 AN: 10584

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.114 AC: 7776 AN: 67998

Other (OTH) AF: 0.109 AC: 229 AN: 2108

Alfa AF: 0.108 Hom.: 690

Bravo AF: 0.109

Asia WGS AF: 0.127 AC: 441 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.65
DANN	Benign	0.40
PhyloP100		-0.094

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: rs3745004; hg19: chr18-43660400;