NM_004046.6:c.*133A>G

Variant names:

• chr18-46084149-T-C
• rs12954944
• NM_004046.6:c.*133A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004046.6(ATP5F1A):​c.*133A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 675,934 control chromosomes in the GnomAD database, including 55,363 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11704 hom., cov: 33)
  • Exomes 𝑓: 0.40 (43659 hom.)
• Consequence: ATP5F1A NM_004046.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.63
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 18-46084149-T-C is Benign according to our data. Variant chr18-46084149-T-C is described in ClinVar as Benign. ClinVar VariationId is 1263382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004046.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5F1A	NM_004046.6	MANE Select	c.*133A>G		3_prime_UTR	Exon 12 of 12	NP_004037.1	P25705-1
	ATP5F1A	NM_001001937.2		c.*133A>G		3_prime_UTR	Exon 13 of 13	NP_001001937.1	P25705-1
	ATP5F1A	NM_001257334.2		c.*133A>G		3_prime_UTR	Exon 12 of 12	NP_001244263.1	P25705-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP5F1A	ENST00000398752.11	TSL:1 MANE Select	c.*133A>G		3_prime_UTR	Exon 12 of 12	ENSP00000381736.5	P25705-1
	ATP5F1A	ENST00000858812.1		c.*133A>G		splice_region	Exon 11 of 11	ENSP00000528871.1
	ATP5F1A	ENST00000858817.1		c.*133A>G		splice_region	Exon 12 of 12	ENSP00000528876.1

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58663 AN: 151998 Hom.: 11698 Cov.: 33

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.465

Gnomad EAS AF: 0.0620

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.424

Gnomad OTH AF: 0.409

GnomAD4 exome AF: 0.396 AC: 207376 AN: 523818 Hom.: 43659 Cov.: 7 AF XY: 0.398 AC XY: 107638 AN XY: 270422

African (AFR) AF: 0.361 AC: 4536 AN: 12556

American (AMR) AF: 0.313 AC: 4237 AN: 13544

Ashkenazi Jewish (ASJ) AF: 0.459 AC: 6268 AN: 13652

East Asian (EAS) AF: 0.0499 AC: 1463 AN: 29322

South Asian (SAS) AF: 0.434 AC: 16510 AN: 38084

European-Finnish (FIN) AF: 0.379 AC: 12307 AN: 32466

Middle Eastern (MID) AF: 0.510 AC: 1076 AN: 2110

European-Non Finnish (NFE) AF: 0.424 AC: 150066 AN: 354222

Other (OTH) AF: 0.392 AC: 10913 AN: 27862

GnomAD4 genome AF: 0.386 AC: 58700 AN: 152116 Hom.: 11704 Cov.: 33 AF XY: 0.382 AC XY: 28394 AN XY: 74364

African (AFR) AF: 0.372 AC: 15447 AN: 41474

American (AMR) AF: 0.340 AC: 5198 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 1611 AN: 3468

East Asian (EAS) AF: 0.0619 AC: 321 AN: 5182

South Asian (SAS) AF: 0.440 AC: 2121 AN: 4820

European-Finnish (FIN) AF: 0.361 AC: 3816 AN: 10568

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

European-Non Finnish (NFE) AF: 0.424 AC: 28806 AN: 68014

Other (OTH) AF: 0.406 AC: 857 AN: 2110

Alfa AF: 0.416 Hom.: 15003

Bravo AF: 0.377

Asia WGS AF: 0.257 AC: 899 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.1
DANN	Benign	0.58
PhyloP100		-1.6
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: rs12954944; hg19: chr18-43664115;