chr18-46083996-C-A

Variant names:

• chr18-46083996-C-A
• rs2578195
• NM_004046.6:c.*286G>T

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.*286G>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 0.519 in 167,914 control chromosomes in the GnomAD database, including 23,497 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.57 (22321 hom., cov: 26)
  • Exomes 𝑓: 0.28 (1176 hom.)
• Consequence: ATP5F1A NM_004046.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.72
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 18-46083996-C-A is Benign according to our data. Variant chr18-46083996-C-A is described in ClinVar as Benign. ClinVar VariationId is 1255357.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.642 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.*286G>T		3_prime_UTR	Exon 12 of 12	NP_004037.1	P25705-1
	ATP5F1A	NM_001001937.2		c.*286G>T		3_prime_UTR	Exon 13 of 13	NP_001001937.1	P25705-1
	ATP5F1A	NM_001257334.2		c.*286G>T		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.*286G>T		3_prime_UTR	Exon 12 of 12	ENSP00000381736.5	P25705-1
	ATP5F1A	ENST00000282050.6	TSL:5	c.*286G>T		downstream_gene	N/A	ENSP00000282050.2	P25705-1
	ATP5F1A	ENST00000858814.1		c.*286G>T		downstream_gene	N/A	ENSP00000528873.1

Frequencies

GnomAD3 genomes AF: 0.568 AC: 79034 AN: 139256 Hom.: 22313 Cov.: 26

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.532

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.588

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.631

Gnomad NFE AF: 0.556

Gnomad OTH AF: 0.568

GnomAD4 exome AF: 0.284 AC: 8126 AN: 28618 Hom.: 1176 Cov.: 0 AF XY: 0.287 AC XY: 4272 AN XY: 14872

African (AFR) AF: 0.411 AC: 308 AN: 750

American (AMR) AF: 0.263 AC: 221 AN: 840

Ashkenazi Jewish (ASJ) AF: 0.304 AC: 340 AN: 1118

East Asian (EAS) AF: 0.223 AC: 487 AN: 2182

South Asian (SAS) AF: 0.280 AC: 322 AN: 1152

European-Finnish (FIN) AF: 0.253 AC: 438 AN: 1730

Middle Eastern (MID) AF: 0.344 AC: 42 AN: 122

European-Non Finnish (NFE) AF: 0.289 AC: 5440 AN: 18852

Other (OTH) AF: 0.282 AC: 528 AN: 1872

GnomAD4 genome AF: 0.568 AC: 79058 AN: 139296 Hom.: 22321 Cov.: 26 AF XY: 0.562 AC XY: 37718 AN XY: 67164

African (AFR) AF: 0.649 AC: 23218 AN: 35780

American (AMR) AF: 0.513 AC: 7063 AN: 13758

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 2002 AN: 3404

East Asian (EAS) AF: 0.442 AC: 2087 AN: 4726

South Asian (SAS) AF: 0.515 AC: 2329 AN: 4520

European-Finnish (FIN) AF: 0.487 AC: 3888 AN: 7982

Middle Eastern (MID) AF: 0.627 AC: 168 AN: 268

European-Non Finnish (NFE) AF: 0.556 AC: 36740 AN: 66040

Other (OTH) AF: 0.565 AC: 1087 AN: 1924

Alfa AF: 0.0155 Hom.: 30

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
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.70
DANN	Benign	0.18
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: rs2578195; hg19: chr18-43663962;