dbSNP rs202110837: ATP5F1A:c.483+15C>T (chr18-46089808-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004046.6(ATP5F1A):c.483+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,609,272 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 4 hom. )

Consequence

ATP5F1A
NM_004046.6 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.57

Publications

1 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 18-46089808-G-A is Benign according to our data. Variant chr18-46089808-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 381166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000991 (151/152302) while in subpopulation AMR AF = 0.00327 (50/15280). AF 95% confidence interval is 0.00255. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 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.483+15C>T	intron	N/A	NP_004037.1	P25705-1
ATP5F1A	NM_001001937.2		c.483+15C>T	intron	N/A	NP_001001937.1	P25705-1
ATP5F1A	NM_001257334.2		c.418-76C>T	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.483+15C>T	intron	N/A	ENSP00000381736.5	P25705-1
ATP5F1A	ENST00000282050.6	TSL:5	c.483+15C>T	intron	N/A	ENSP00000282050.2	P25705-1
ATP5F1A	ENST00000858814.1		c.483+15C>T	intron	N/A	ENSP00000528873.1

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

151

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00328

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.000711

AC:

176

AN:

247512

AF XY:

0.000717

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000713

Gnomad ASJ exome

AF:

0.00114

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00109

Gnomad OTH exome

AF:

0.00266

GnomAD4 exome

AF:

0.00115

AC:

1669

AN:

1456970

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

780

AN XY:

724526

show subpopulations

African (AFR)

AF:

0.000271

AC:

AN:

33204

American (AMR)

AF:

0.00118

AC:

AN:

43956

Ashkenazi Jewish (ASJ)

AF:

0.00124

AC:

AN:

25802

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.0000350

AC:

AN:

85788

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53302

Middle Eastern (MID)

AF:

0.000349

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00135

AC:

1497

AN:

1109406

Other (OTH)

AF:

0.00121

AC:

AN:

60134

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

191

287

382

478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.000991

AC:

151

AN:

152302

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41572

American (AMR)

AF:

0.00327

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00109

AC:

AN:

68024

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

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:

0.000897

Hom.:

Bravo

AF:

0.00158

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.029

(source)

DANN

Benign

0.48

PhyloP100

-1.6

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