chr17-18021850-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000474627.8(ATPAF2):c.511G>A(p.Val171Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0082 in 1,613,912 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V171L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0060 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0084 ( 64 hom. )

Consequence

ATPAF2
ENST00000474627.8 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:9

Conservation

PhyloP100: 1.17

Publications

10 publications found

Variant links:

Genes affected

ATPAF2 (HGNC:18802): (ATP synthase mitochondrial F1 complex assembly factor 2) This gene encodes an assembly factor for the F(1) component of the mitochondrial ATP synthase. This protein binds specifically to the F1 alpha subunit and is thought to prevent this subunit from forming nonproductive homooligomers during enzyme assembly. This gene is located within the Smith-Magenis syndrome region on chromosome 17. An alternatively spliced transcript variant has been described, but its biological validity has not been determined. [provided by RefSeq, Jul 2008]

ATPAF2 Gene-Disease associations (from GenCC):

mitochondrial proton-transporting ATP synthase complex deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mitochondrial complex V (ATP synthase) deficiency, nuclear type 1
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
mitochondrial disease
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ATPAF2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069763362).

BP6

Variant 17-18021850-C-T is Benign according to our data. Variant chr17-18021850-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000474627.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATPAF2	NM_145691.4	MANE Select	c.511G>A	p.Val171Met	missense	Exon 6 of 8	NP_663729.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATPAF2	ENST00000474627.8	TSL:1 MANE Select	c.511G>A	p.Val171Met	missense	Exon 6 of 8	ENSP00000417190.2
ATPAF2	ENST00000462733.5	TSL:1	n.*34-612G>A		intron	N/A	ENSP00000463920.1
ATPAF2	ENST00000444058.1	TSL:3	c.511G>A	p.Val171Met	missense	Exon 7 of 7	ENSP00000397198.1

Frequencies

GnomAD3 genomes

AF:

0.00600

AC:

914

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00200

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.00805

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00946

Gnomad OTH

AF:

0.00956

GnomAD2 exomes

AF:

0.00566

AC:

1424

AN:

251382

AF XY:

0.00575

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00483

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00166

Gnomad NFE exome

AF:

0.00954

Gnomad OTH exome

AF:

0.00863

GnomAD4 exome

AF:

0.00843

AC:

12321

AN:

1461574

Hom.:

Cov.:

AF XY:

0.00815

AC XY:

5929

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33476

American (AMR)

AF:

0.00528

AC:

236

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00287

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.00119

AC:

103

AN:

86250

European-Finnish (FIN)

AF:

0.00152

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00955

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0101

AC:

11227

AN:

1111768

Other (OTH)

AF:

0.00815

AC:

492

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

600

1201

1801

2402

3002

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

422

844

1266

1688

2110

<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:

0.00599

AC:

912

AN:

152338

Hom.:

Cov.:

AF XY:

0.00577

AC XY:

430

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00197

AC:

AN:

41576

American (AMR)

AF:

0.00804

AC:

123

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00946

AC:

644

AN:

68042

Other (OTH)

AF:

0.00946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

146

194

243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00755

Hom.:

Bravo

AF:

0.00645

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00767

AC:

ExAC

AF:

0.00557

AC:

676

EpiCase

AF:

0.0100

EpiControl

AF:

0.0116

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 1 (3)

ATPAF2-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.35

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0070

MetaSVM

Benign

-0.73

MutationAssessor

Pathogenic

3.0

PhyloP100

1.2

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.36

Sift

Benign

0.060

Sift4G

Uncertain

0.041

Polyphen

0.69

Vest4

0.30

MVP

0.82

MPC

0.49

ClinPred

0.045

GERP RS

-1.6

Varity_R

0.20

gMVP

0.78

Mutation Taster

=97/3

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

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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over