chr18-46084207-C-A

Variant names:

• chr18-46084207-C-A
• rs15042
• NM_004046.6:c.*75G>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004046.6(ATP5F1A):​c.*75G>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 0.00146 in 1,280,988 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0068 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00074 (16 hom.)
• Consequence: ATP5F1A NM_004046.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.268
• 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: 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=-0.82).
• BP6: Variant 18-46084207-C-A is Benign according to our data. Variant chr18-46084207-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1199822.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00681 (1037/152232) while in subpopulation AFR AF = 0.0234 (971/41564). AF 95% confidence interval is 0.0221. There are 7 homozygotes in GnomAd4. There are 479 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,Unknown,AR gene

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.*75G>T		3_prime_UTR	Exon 12 of 12	NP_004037.1	P25705-1
	ATP5F1A	NM_001001937.2		c.*75G>T		3_prime_UTR	Exon 13 of 13	NP_001001937.1	P25705-1
	ATP5F1A	NM_001257334.2		c.*75G>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.*75G>T		3_prime_UTR	Exon 12 of 12	ENSP00000381736.5	P25705-1
	ATP5F1A	ENST00000282050.6	TSL:5	c.*75G>T		3_prime_UTR	Exon 13 of 13	ENSP00000282050.2	P25705-1
	ATP5F1A	ENST00000858814.1		c.*75G>T		3_prime_UTR	Exon 12 of 12	ENSP00000528873.1

Frequencies

GnomAD3 genomes AF: 0.00677 AC: 1030 AN: 152114 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0233

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000739 AC: 834 AN: 1128756 Hom.: 16 Cov.: 14 AF XY: 0.000647 AC XY: 371 AN XY: 573160

African (AFR) AF: 0.0254 AC: 660 AN: 25938

American (AMR) AF: 0.00117 AC: 43 AN: 36600

Ashkenazi Jewish (ASJ) AF: 0.0000457 AC: 1 AN: 21872

East Asian (EAS) AF: 0.00 AC: 0 AN: 37924

South Asian (SAS) AF: 0.0000966 AC: 7 AN: 72472

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48824

Middle Eastern (MID) AF: 0.00234 AC: 8 AN: 3416

European-Non Finnish (NFE) AF: 0.0000360 AC: 30 AN: 832766

Other (OTH) AF: 0.00174 AC: 85 AN: 48944

GnomAD4 genome AF: 0.00681 AC: 1037 AN: 152232 Hom.: 7 Cov.: 33 AF XY: 0.00644 AC XY: 479 AN XY: 74430

African (AFR) AF: 0.0234 AC: 971 AN: 41564

American (AMR) AF: 0.00341 AC: 52 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68024

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00199 Hom.: 1

Bravo AF: 0.00771

ClinVar

ClinVar submissions

Significance: Likely 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	-0.82
CADD	Benign	1.0
DANN	Benign	0.53
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs15042; hg19: chr18-43664173;