NM_001369.3:c.3241A>G

Variant names:

Variant summary

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

The NM_001369.3(DNAH5):c.3241A>G(p.Met1081Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 1,613,786 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 49 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 56 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.63

Publications

7 publications found

Variant links:

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

DNAH5 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAH5 links:

DNAH5-AS1 (HGNC:40187):

DNAH5-AS1 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 (MetaRNN=0.0018901825).

BP6

Variant 5-13882749-T-C is Benign according to our data. Variant chr5-13882749-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0136 (2078/152318) while in subpopulation AFR AF = 0.0459 (1907/41562). AF 95% confidence interval is 0.0442. There are 49 homozygotes in GnomAd4. There are 985 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 49 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369.3. 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
	DNAH5	NM_001369.3	MANE Select	c.3241A>G	p.Met1081Val	missense	Exon 21 of 79	NP_001360.1	Q8TE73
	DNAH5-AS1	NR_199035.1		n.118-13840T>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.3241A>G	p.Met1081Val	missense	Exon 21 of 79	ENSP00000265104.4	Q8TE73
DNAH5	ENST00000681290.1		c.3196A>G	p.Met1066Val	missense	Exon 21 of 79	ENSP00000505288.1	A0A7P0Z455
DNAH5-AS1	ENST00000503244.2	TSL:4	n.254-13840T>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2065

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0457

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00850

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.0119

GnomAD2 exomes

AF:

0.00365

AC:

916

AN:

251170

AF XY:

0.00278

show subpopulations

Gnomad AFR exome

AF:

0.0482

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00262

GnomAD4 exome

AF:

0.00150

AC:

2195

AN:

1461468

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

934

AN XY:

727082

show subpopulations

African (AFR)

AF:

0.0509

AC:

1702

AN:

33458

American (AMR)

AF:

0.00293

AC:

131

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000900

AC:

100

AN:

1111676

Other (OTH)

AF:

0.00384

AC:

232

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

195

293

390

488

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.0136

AC:

2078

AN:

152318

Hom.:

Cov.:

AF XY:

0.0132

AC XY:

985

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0459

AC:

1907

AN:

41562

American (AMR)

AF:

0.00849

AC:

130

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68010

Other (OTH)

AF:

0.0118

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

191

287

382

478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00527

Hom.:

Bravo

AF:

0.0159

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0411

AC:

181

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00438

AC:

532

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (3)

Primary ciliary dyskinesia 3 (3)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.72

CADD

Benign

2.7

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.034

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.29

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.55

PhyloP100

2.6

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.69

REVEL

Benign

0.065

Sift

Benign

0.61

Polyphen

0.0

Vest4

0.15

MVP

0.21

MPC

0.095

ClinPred

0.0040

GERP RS

-1.5

Varity_R

0.063

gMVP

0.21

Mutation Taster

=90/10

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