rs144575803

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_001369.3(DNAH5):c.1198G>A(p.Val400Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00051 in 1,612,650 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00051 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 4 hom. )

Consequence

DNAH5
NM_001369.3 missense, splice_region

Scores

Splicing: ADA: 0.9989

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:4

Conservation

PhyloP100: 7.81

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 5-13914642-C-T is Benign according to our data. Variant chr5-13914642-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 219733.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00051 (745/1460498) while in subpopulation MID AF = 0.00562 (32/5694). AF 95% confidence interval is 0.00409. There are 4 homozygotes in GnomAdExome4. There are 390 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3 link	c.1198G>A	p.Val400Met	missense_variant, splice_region_variant	Exon 10 of 79	ENST00000265104.5	NP_001360.1	Q8TE73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5 link	c.1198G>A	p.Val400Met	missense_variant, splice_region_variant	Exon 10 of 79	1	NM_001369.3	ENSP00000265104.4		Q8TE73

Frequencies

GnomAD3 genomes

AF:

0.000520

AC:

AN:

152034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000983

Gnomad ASJ

AF:

0.00952

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000870

AC:

218

AN:

250714

AF XY:

0.000812

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000898

Gnomad ASJ exome

AF:

0.00975

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000547

Gnomad OTH exome

AF:

0.000982

GnomAD4 exome

AF:

0.000510

AC:

745

AN:

1460498

Hom.:

Cov.:

AF XY:

0.000537

AC XY:

390

AN XY:

726578

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33434

American (AMR)

AF:

0.000761

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00942

AC:

246

AN:

26102

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39648

South Asian (SAS)

AF:

0.000684

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00562

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.000273

AC:

303

AN:

1111034

Other (OTH)

AF:

0.00108

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

120

160

200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000513

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000578

AC XY:

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41546

American (AMR)

AF:

0.000982

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00952

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

67924

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000831

Hom.:

Bravo

AF:

0.000593

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000717

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 3

Uncertain:6

May 18, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 18, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Feb 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The DNAH5 c.1198G>A; p.Val400Met variant (rs144575803) is reported in the literature in two siblings affected with tetralogy of Fallot (Izarzugaza 2020). This variant is reported in ClinVar (Variation ID: 219733) and is found in the general population with an overall allele frequency of 0.08% (226/282,092 alleles, including one homozygote) in the Genome Aggregation Database (v2.1.1). This is a missense variant in a highly conserved nucleotide at the first base of exon 10, and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the canonical acceptor splice site. However, further study is needed to determine the functional impact. While the high population frequency suggests that this is likely a benign variant, given the limited clinical data and lack of functional data, the significance of this variant is uncertain at this time. References: Izarzugaza JMG et al. Systems genetics analysis identifies calcium-signaling defects as novel cause of congenital heart disease. Genome Med. 2020 Aug 28;12(1):76. PMID: 32859249. -

Jan 29, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:3

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 06, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 02, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DNAH5-related disorder

Benign:1

Feb 09, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.059

MetaRNN

Benign

0.039

MetaSVM

Uncertain

-0.19

MutationAssessor

Pathogenic

3.2

PhyloP100

7.8

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.6

REVEL

Uncertain

0.32

Sift

Benign

0.086

Polyphen

1.0

Vest4

0.85

MVP

0.80

MPC

0.42

ClinPred

0.091

GERP RS

5.5

Varity_R

0.55

gMVP

0.78

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.89

SpliceAI score (max)

0.10

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over