5-13871648-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001369.3(DNAH5):c.3514C>A(p.Gln1172Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00235 in 1,613,768 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q1172Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 10 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 5.32

Publications

8 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012865871).

BP6

Variant 5-13871648-G-T is Benign according to our data. Variant chr5-13871648-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163152.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00175 (267/152298) while in subpopulation NFE AF = 0.00285 (194/68022). AF 95% confidence interval is 0.00252. There are 1 homozygotes in GnomAd4. There are 124 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 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.3514C>A	p.Gln1172Lys	missense	Exon 23 of 79	NP_001360.1
	DNAH5-AS1	NR_199035.1		n.117+11093G>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.3514C>A	p.Gln1172Lys	missense	Exon 23 of 79	ENSP00000265104.4
DNAH5	ENST00000681290.1		c.3469C>A	p.Gln1157Lys	missense	Exon 23 of 79	ENSP00000505288.1
DNAH5-AS1	ENST00000503244.2	TSL:4	n.253+11093G>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00285

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00223

AC:

560

AN:

251064

AF XY:

0.00218

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000899

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00421

Gnomad NFE exome

AF:

0.00345

Gnomad OTH exome

AF:

0.00343

GnomAD4 exome

AF:

0.00242

AC:

3533

AN:

1461470

Hom.:

Cov.:

AF XY:

0.00238

AC XY:

1729

AN XY:

727026

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33454

American (AMR)

AF:

0.000941

AC:

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000672

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00436

AC:

233

AN:

53414

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00276

AC:

3069

AN:

1111754

Other (OTH)

AF:

0.00197

AC:

119

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

189

379

568

758

947

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.00175

AC:

267

AN:

152298

Hom.:

Cov.:

AF XY:

0.00166

AC XY:

124

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41560

American (AMR)

AF:

0.000785

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00311

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00285

AC:

194

AN:

68022

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

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:

0.00239

Hom.:

Bravo

AF:

0.00152

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00241

AC:

292

Asia WGS

AF:

0.000289

AC:

AN:

3474

EpiCase

AF:

0.00240

EpiControl

AF:

0.00267

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia 3 (5)

Primary ciliary dyskinesia (3)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.096

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.19

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

M_CAP

Benign

0.019

MetaRNN

Benign

0.013

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

5.3

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.5

REVEL

Benign

0.15

Sift

Benign

0.56

Polyphen

0.0

Vest4

0.49

MVP

0.35

MPC

0.13

ClinPred

0.017

GERP RS

3.2

Varity_R

0.12

gMVP

0.46

Mutation Taster

=96/4

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