rs202210184

Variant names:

• chr18-46083995-AC-A
• rs202210184
• NM_004046.6:c.*286delG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004046.6(ATP5F1A):​c.*286delG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 196,366 control chromosomes in the GnomAD database, including 133 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (128 hom., cov: 26)
  • Exomes 𝑓: 0.014 (5 hom.)
• Consequence: ATP5F1A NM_004046.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.72
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P
• 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 -10 ACMG points.

• BP6: Variant 18-46083995-AC-A is Benign according to our data. Variant chr18-46083995-AC-A is described in ClinVar as Benign. ClinVar VariationId is 1239941.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 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.*286delG		3_prime_UTR	Exon 12 of 12	NP_004037.1	P25705-1
	ATP5F1A	NM_001001937.2		c.*286delG		3_prime_UTR	Exon 13 of 13	NP_001001937.1	P25705-1
	ATP5F1A	NM_001257334.2		c.*286delG		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.*286delG		3_prime_UTR	Exon 12 of 12	ENSP00000381736.5	P25705-1
	ATP5F1A	ENST00000282050.6	TSL:5	c.*286delG		downstream_gene	N/A	ENSP00000282050.2	P25705-1
	ATP5F1A	ENST00000858814.1		c.*286delG		downstream_gene	N/A	ENSP00000528873.1

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2438 AN: 148592 Hom.: 128 Cov.: 26

Gnomad AFR AF: 0.0548

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00908

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0131

Gnomad NFE AF: 0.00134

Gnomad OTH AF: 0.0119

GnomAD4 exome AF: 0.0137 AC: 654 AN: 47676 Hom.: 5 Cov.: 0 AF XY: 0.0136 AC XY: 335 AN XY: 24678

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0275 AC: 33 AN: 1202

American (AMR) AF: 0.0142 AC: 20 AN: 1406

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 26 AN: 1738

East Asian (EAS) AF: 0.00302 AC: 11 AN: 3640

South Asian (SAS) AF: 0.0238 AC: 45 AN: 1888

European-Finnish (FIN) AF: 0.0134 AC: 39 AN: 2914

Middle Eastern (MID) AF: 0.0142 AC: 3 AN: 212

European-Non Finnish (NFE) AF: 0.0135 AC: 426 AN: 31532

Other (OTH) AF: 0.0162 AC: 51 AN: 3144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0164 AC: 2441 AN: 148690 Hom.: 128 Cov.: 26 AF XY: 0.0156 AC XY: 1131 AN XY: 72562

African (AFR) AF: 0.0547 AC: 2182 AN: 39856

American (AMR) AF: 0.00555 AC: 83 AN: 14948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00888 AC: 42 AN: 4730

European-Finnish (FIN) AF: 0.00169 AC: 17 AN: 10052

Middle Eastern (MID) AF: 0.0106 AC: 3 AN: 284

European-Non Finnish (NFE) AF: 0.00134 AC: 90 AN: 67280

Other (OTH) AF: 0.0118 AC: 24 AN: 2042

Alfa AF: 0.000462 Hom.: 0

Asia WGS AF: 0.00843 AC: 29 AN: 3454

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.7

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: rs202210184; hg19: chr18-43663961;