dbSNP rs145327382: DNAH3:p.Lys3842Arg (chr16-20936845-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001347886.2(DNAH3):c.11525A>G(p.Lys3842Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,610,568 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

DNAH3
NM_001347886.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.582

Publications

2 publications found

Variant links:

Genes affected

DNAH3 (HGNC:2949): (dynein axonemal heavy chain 3) This gene belongs to the dynein family, whose members encode large proteins that are constituents of the microtubule-associated motor protein complex. This complex is composed of dynein heavy, intermediate and light chains, which can be axonemal or cytoplasmic. This protein is an axonemal dynein heavy chain. It is involved in producing force for ciliary beating by using energy from ATP hydrolysis. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

DNAH3 Gene-Disease associations (from GenCC):

male infertility
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

DNAH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013460994).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347886.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH3	NM_001347886.2	MANE Select	c.11525A>G	p.Lys3842Arg	missense	Exon 60 of 62	NP_001334815.1	A0A8V8TLI9
	DNAH3	NM_017539.2		c.11663A>G	p.Lys3888Arg	missense	Exon 60 of 62	NP_060009.1	Q8TD57-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH3	ENST00000698260.1	MANE Select	c.11525A>G	p.Lys3842Arg	missense	Exon 60 of 62	ENSP00000513632.1	A0A8V8TLI9
DNAH3	ENST00000261383.3	TSL:1	c.11663A>G	p.Lys3888Arg	missense	Exon 60 of 62	ENSP00000261383.3	Q8TD57-1
DNAH3	ENST00000685858.1		c.11705A>G	p.Lys3902Arg	missense	Exon 60 of 62	ENSP00000508756.1	A0A8I5KSE2

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00143

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000914

AC:

224

AN:

245066

AF XY:

0.000929

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000732

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000330

Gnomad FIN exome

AF:

0.0000473

Gnomad NFE exome

AF:

0.00164

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.00116

AC:

1690

AN:

1458340

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

858

AN XY:

725082

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33420

American (AMR)

AF:

0.000899

AC:

AN:

44488

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26010

East Asian (EAS)

AF:

0.000101

AC:

AN:

39618

South Asian (SAS)

AF:

0.000152

AC:

AN:

85494

European-Finnish (FIN)

AF:

0.000113

AC:

AN:

53186

Middle Eastern (MID)

AF:

0.000758

AC:

AN:

5278

European-Non Finnish (NFE)

AF:

0.00142

AC:

1575

AN:

1110622

Other (OTH)

AF:

0.000764

AC:

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

168

252

336

420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.000742

AC:

113

AN:

152228

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41538

American (AMR)

AF:

0.000131

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00143

AC:

AN:

67992

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.00126

Hom.:

Bravo

AF:

0.000816

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000931

AC:

113

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.030

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0067

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.74

PhyloP100

0.58

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.0

REVEL

Benign

0.069

Sift

Benign

0.38

Polyphen

0.14

Vest4

0.45

MVP

0.095

MPC

0.076

ClinPred

0.015

GERP RS

4.6

Varity_R

0.13

gMVP

0.20

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