rs35900306

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001369.3(DNAH5):​c.7274G>A​(p.Arg2425His) variant causes a missense change. The variant allele was found at a frequency of 0.0044 in 1,614,062 control chromosomes in the GnomAD database, including 210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2425C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.022 ( 99 hom., cov: 32)
Exomes 𝑓: 0.0026 ( 111 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

1
4
12

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.98
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.002856791).
BP6
Variant 5-13811780-C-T is Benign according to our data. Variant chr5-13811780-C-T is described in ClinVar as [Benign]. Clinvar id is 226606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13811780-C-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0698 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNAH5NM_001369.3 linkuse as main transcriptc.7274G>A p.Arg2425His missense_variant 44/79 ENST00000265104.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNAH5ENST00000265104.5 linkuse as main transcriptc.7274G>A p.Arg2425His missense_variant 44/791 NM_001369.3 P4
DNAH5ENST00000681290.1 linkuse as main transcriptc.7229G>A p.Arg2410His missense_variant 44/79 A1

Frequencies

GnomAD3 genomes
AF:
0.0215
AC:
3276
AN:
152088
Hom.:
98
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0720
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0135
Gnomad ASJ
AF:
0.00259
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.0000944
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.000573
Gnomad OTH
AF:
0.0172
GnomAD3 exomes
AF:
0.00642
AC:
1613
AN:
251414
Hom.:
47
AF XY:
0.00500
AC XY:
680
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.0773
Gnomad AMR exome
AF:
0.00656
Gnomad ASJ exome
AF:
0.00189
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000703
Gnomad OTH exome
AF:
0.00407
GnomAD4 exome
AF:
0.00261
AC:
3815
AN:
1461856
Hom.:
111
Cov.:
32
AF XY:
0.00228
AC XY:
1656
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.0748
Gnomad4 AMR exome
AF:
0.00720
Gnomad4 ASJ exome
AF:
0.00191
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000255
Gnomad4 FIN exome
AF:
0.0000749
Gnomad4 NFE exome
AF:
0.000437
Gnomad4 OTH exome
AF:
0.00594
GnomAD4 genome
AF:
0.0216
AC:
3282
AN:
152206
Hom.:
99
Cov.:
32
AF XY:
0.0207
AC XY:
1543
AN XY:
74416
show subpopulations
Gnomad4 AFR
AF:
0.0719
Gnomad4 AMR
AF:
0.0135
Gnomad4 ASJ
AF:
0.00259
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.0000944
Gnomad4 NFE
AF:
0.000573
Gnomad4 OTH
AF:
0.0170
Alfa
AF:
0.00426
Hom.:
20
Bravo
AF:
0.0252
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.0731
AC:
322
ESP6500EA
AF:
0.000814
AC:
7
ExAC
AF:
0.00752
AC:
913
Asia WGS
AF:
0.00520
AC:
18
AN:
3478
EpiCase
AF:
0.000872
EpiControl
AF:
0.000889

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Benign:3
Benign, criteria provided, single submitterclinical testingAmbry GeneticsDec 24, 2014This alteration is classified as 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. -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineFeb 21, 2013Arg2425His in exon 44 of DNAH5: This variant is not expected to have clinical si gnificance because it has been identified in 7.3% (322/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs35900306). -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxDec 31, 2018- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Primary ciliary dyskinesia 3 Benign:2
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 21, 2023- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.56
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.092
T
Eigen
Uncertain
0.22
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.86
D
MetaRNN
Benign
0.0029
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.2
M
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-2.0
N
REVEL
Benign
0.14
Sift
Benign
0.51
T
Polyphen
0.13
B
Vest4
0.36
MVP
0.54
MPC
0.12
ClinPred
0.033
T
GERP RS
5.8
Varity_R
0.15
gMVP
0.58

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs35900306; hg19: chr5-13811889; COSMIC: COSV105874400; COSMIC: COSV105874400; API