rs193222617

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_031294.4(DRC3):c.205A>G(p.Lys69Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0051 in 1,613,608 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0040 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 24 hom. )

Consequence

DRC3
NM_031294.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.82

Publications

8 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:

LOC107984989 (HGNC:):

LOC107984989 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01029402).

BP6

Variant 17-17983872-A-G is Benign according to our data. Variant chr17-17983872-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2647535.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DRC3	NM_031294.4	MANE Select	c.205A>G	p.Lys69Glu	missense	Exon 4 of 14	NP_112584.3
DRC3	NM_001130090.1		c.205A>G	p.Lys69Glu	missense	Exon 5 of 15	NP_001123562.1	B3KSC6
DRC3	NM_001130091.2		c.205A>G	p.Lys69Glu	missense	Exon 5 of 14	NP_001123563.1	Q9H069-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DRC3	ENST00000399187.6	TSL:1 MANE Select	c.205A>G	p.Lys69Glu	missense	Exon 4 of 14	ENSP00000382140.1	Q9H069-1
DRC3	ENST00000399182.5	TSL:1	c.205A>G	p.Lys69Glu	missense	Exon 4 of 13	ENSP00000382136.1	Q9H069-2
DRC3	ENST00000584166.5	TSL:5	c.205A>G	p.Lys69Glu	missense	Exon 5 of 14	ENSP00000462661.1	Q9H069-2

Frequencies

GnomAD3 genomes

AF:

0.00396

AC:

602

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00195

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00726

Gnomad ASJ

AF:

0.00548

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00544

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00363

AC:

903

AN:

248920

AF XY:

0.00338

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.00536

Gnomad ASJ exome

AF:

0.00447

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000603

Gnomad NFE exome

AF:

0.00542

Gnomad OTH exome

AF:

0.00364

GnomAD4 exome

AF:

0.00522

AC:

7622

AN:

1461300

Hom.:

Cov.:

AF XY:

0.00497

AC XY:

3611

AN XY:

726936

show subpopulations

African (AFR)

AF:

0.00191

AC:

AN:

33464

American (AMR)

AF:

0.00577

AC:

258

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00486

AC:

127

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000693

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00611

AC:

6789

AN:

1111562

Other (OTH)

AF:

0.00552

AC:

333

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

362

723

1085

1446

1808

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

266

532

798

1064

1330

<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:

0.00395

AC:

602

AN:

152308

Hom.:

Cov.:

AF XY:

0.00387

AC XY:

288

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

41576

American (AMR)

AF:

0.00725

AC:

111

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00548

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00544

AC:

370

AN:

68016

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00497

Hom.:

Bravo

AF:

0.00471

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.00301

AC:

ESP6500EA

AF:

0.00492

AC:

ExAC

AF:

0.00334

AC:

404

EpiCase

AF:

0.00594

EpiControl

AF:

0.00474

ClinVar

ClinVar submissions as Germline

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

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

M_CAP

Benign

0.022

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.99

PhyloP100

7.8

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.32

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.051

Polyphen

1.0

Vest4

0.72

MVP

0.80

MPC

0.84

ClinPred

0.019

GERP RS

5.2

Varity_R

0.60

gMVP

0.75

Mutation Taster

=99/1

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

Computational scores

Splicing

Publications

Other links and lift over