Genetic Variant NM_004046.6:c.1580+23C>A (chr18-46084481-G-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004046.6(ATP5F1A):c.1580+23C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000884 in 1,577,770 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0051 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00044 ( 6 hom. )

Consequence

ATP5F1A
NM_004046.6 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0110

Publications

0 publications found

Variant links:

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)

ATP5F1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 18-46084481-G-T is Benign according to our data. Variant chr18-46084481-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1201248.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00505 (769/152266) while in subpopulation AFR AF = 0.0178 (738/41558). AF 95% confidence interval is 0.0167. There are 2 homozygotes in GnomAd4. There are 364 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATP5F1A	NM_004046.6	MANE Select	c.1580+23C>A	intron	N/A	NP_004037.1	P25705-1
ATP5F1A	NM_001001937.2		c.1580+23C>A	intron	N/A	NP_001001937.1	P25705-1
ATP5F1A	NM_001257334.2		c.1514+23C>A	intron	N/A	NP_001244263.1	P25705-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATP5F1A	ENST00000398752.11	TSL:1 MANE Select	c.1580+23C>A	intron	N/A	ENSP00000381736.5	P25705-1
ATP5F1A	ENST00000282050.6	TSL:5	c.1580+23C>A	intron	N/A	ENSP00000282050.2	P25705-1
ATP5F1A	ENST00000858814.1		c.1562+23C>A	intron	N/A	ENSP00000528873.1

Frequencies

GnomAD3 genomes

AF:

0.00504

AC:

767

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0178

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

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:

0.0000588

Gnomad OTH

AF:

0.00479

GnomAD2 exomes

AF:

0.00140

AC:

308

AN:

219626

AF XY:

0.00100

show subpopulations

Gnomad AFR exome

AF:

0.0173

Gnomad AMR exome

AF:

0.000986

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000384

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000438

AC:

625

AN:

1425504

Hom.:

Cov.:

AF XY:

0.000393

AC XY:

278

AN XY:

707250

show subpopulations

African (AFR)

AF:

0.0157

AC:

494

AN:

31444

American (AMR)

AF:

0.00103

AC:

AN:

35770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23990

East Asian (EAS)

AF:

0.00

AC:

AN:

39386

South Asian (SAS)

AF:

0.00

AC:

AN:

79908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52378

Middle Eastern (MID)

AF:

0.000718

AC:

AN:

5574

European-Non Finnish (NFE)

AF:

0.0000255

AC:

AN:

1098398

Other (OTH)

AF:

0.00106

AC:

AN:

58656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

118

148

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00505

AC:

769

AN:

152266

Hom.:

Cov.:

AF XY:

0.00489

AC XY:

364

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0178

AC:

738

AN:

41558

American (AMR)

AF:

0.00111

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68032

Other (OTH)

AF:

0.00474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

125

166

208

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00282

Hom.:

Bravo

AF:

0.00533

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.27

(source)

DANN

Benign

0.36

PhyloP100

-0.011

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over