chr17-17992891-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_031294.4(DRC3):c.571C>T(p.Arg191Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,613,078 control chromosomes in the GnomAD database, including 126,421 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R191Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.40 ( 13438 hom., cov: 32)

Exomes 𝑓: 0.37 ( 112983 hom. )

Consequence

DRC3
NM_031294.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.50

Publications

46 publications found

Variant links:

Genes affected

DRC3 (HGNC:25384): (dynein regulatory complex subunit 3) Located in axoneme. [provided by Alliance of Genome Resources, Apr 2022]

DRC3 links:

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.0401418E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.848 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC3	NM_031294.4 link	c.571C>T	p.Arg191Trp	missense_variant	Exon 6 of 14	ENST00000399187.6	NP_112584.3	Q9H069-1B3KSC6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DRC3	ENST00000399187.6 link	c.571C>T	p.Arg191Trp	missense_variant	Exon 6 of 14	1	NM_031294.4	ENSP00000382140.1	Q9H069-1
DRC3	ENST00000399182.5 link	c.571C>T	p.Arg191Trp	missense_variant	Exon 6 of 13	1		ENSP00000382136.1	Q9H069-2
DRC3	ENST00000584166.5 link	c.571C>T	p.Arg191Trp	missense_variant	Exon 7 of 14	5		ENSP00000462661.1	Q9H069-2
DRC3	ENST00000583171.5 link	n.127C>T		non_coding_transcript_exon_variant	Exon 1 of 6	3		ENSP00000464101.2	J3QR90

Frequencies

GnomAD3 genomes

AF:

0.402

AC:

61087

AN:

151898

Hom.:

13431

Cov.:

show subpopulations

Gnomad AFR

AF:

0.406

Gnomad AMI

AF:

0.417

Gnomad AMR

AF:

0.494

Gnomad ASJ

AF:

0.414

Gnomad EAS

AF:

0.869

Gnomad SAS

AF:

0.719

Gnomad FIN

AF:

0.398

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.404

GnomAD2 exomes

AF:

0.467

AC:

116249

AN:

249176

AF XY:

0.470

show subpopulations

Gnomad AFR exome

AF:

0.416

Gnomad AMR exome

AF:

0.600

Gnomad ASJ exome

AF:

0.413

Gnomad EAS exome

AF:

0.880

Gnomad FIN exome

AF:

0.382

Gnomad NFE exome

AF:

0.324

Gnomad OTH exome

AF:

0.424

GnomAD4 exome

AF:

0.368

AC:

537712

AN:

1461062

Hom.:

112983

Cov.:

AF XY:

0.378

AC XY:

274985

AN XY:

726842

show subpopulations

African (AFR)

AF:

0.409

AC:

13698

AN:

33460

American (AMR)

AF:

0.587

AC:

26255

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.415

AC:

10839

AN:

26124

East Asian (EAS)

AF:

0.866

AC:

34362

AN:

39696

South Asian (SAS)

AF:

0.706

AC:

60921

AN:

86246

European-Finnish (FIN)

AF:

0.375

AC:

20010

AN:

53382

Middle Eastern (MID)

AF:

0.405

AC:

2335

AN:

5764

European-Non Finnish (NFE)

AF:

0.311

AC:

345165

AN:

1111328

Other (OTH)

AF:

0.400

AC:

24127

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

14948

29896

44845

59793

74741

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11610

23220

34830

46440

58050

<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:

0.402

AC:

61128

AN:

152016

Hom.:

13438

Cov.:

AF XY:

0.416

AC XY:

30884

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.405

AC:

16801

AN:

41448

American (AMR)

AF:

0.495

AC:

7554

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.414

AC:

1438

AN:

3470

East Asian (EAS)

AF:

0.869

AC:

4505

AN:

5182

South Asian (SAS)

AF:

0.719

AC:

3461

AN:

4812

European-Finnish (FIN)

AF:

0.398

AC:

4206

AN:

10564

Middle Eastern (MID)

AF:

0.361

AC:

106

AN:

294

European-Non Finnish (NFE)

AF:

0.321

AC:

21825

AN:

67958

Other (OTH)

AF:

0.404

AC:

852

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1744

3488

5233

6977

8721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

590

1180

1770

2360

2950

<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:

0.358

Hom.:

19830

Bravo

AF:

0.408

TwinsUK

AF:

0.301

AC:

1117

ALSPAC

AF:

0.300

AC:

1157

ESP6500AA

AF:

0.400

AC:

1688

ESP6500EA

AF:

0.326

AC:

2759

ExAC

AF:

0.461

AC:

55756

Asia WGS

AF:

0.704

AC:

2447

AN:

3478

EpiCase

AF:

0.337

EpiControl

AF:

0.341

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.091

T;T;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.80

T;.;.;T

MetaRNN

Benign

0.0000010

T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

3.5

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-6.5

D;D;.;D

REVEL

Benign

0.22

Sift

Uncertain

0.017

D;D;.;D

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

1.0

D;D;D;D

Vest4

0.19

MPC

0.69

ClinPred

0.050

GERP RS

3.0

Varity_R

0.50

gMVP

0.73

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over