rs3756672

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.12472C>T​(p.Arg4158Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00222 in 1,613,842 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4158Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0022 ( 7 hom., cov: 32)
Exomes 𝑓: 0.0022 ( 79 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

5
7
5

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 3.88
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 was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.012498289).
BP6
Variant 5-13718909-G-A is Benign according to our data. Variant chr5-13718909-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 238959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13718909-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0022 (335/152250) while in subpopulation EAS AF = 0.0465 (241/5180). AF 95% confidence interval is 0.0417. There are 7 homozygotes in GnomAd4. There are 185 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
BS2
High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAH5NM_001369.3 linkc.12472C>T p.Arg4158Trp missense_variant Exon 72 of 79 ENST00000265104.5 NP_001360.1 Q8TE73

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAH5ENST00000265104.5 linkc.12472C>T p.Arg4158Trp missense_variant Exon 72 of 79 1 NM_001369.3 ENSP00000265104.4 Q8TE73
DNAH5ENST00000681290.1 linkc.12427C>T p.Arg4143Trp missense_variant Exon 72 of 79 ENSP00000505288.1 A0A7P0Z455

Frequencies

GnomAD3 genomes
AF:
0.00220
AC:
334
AN:
152132
Hom.:
7
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.0468
Gnomad SAS
AF:
0.0143
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00287
GnomAD2 exomes
AF:
0.00449
AC:
1128
AN:
251204
AF XY:
0.00471
show subpopulations
Gnomad AFR exome
AF:
0.000185
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.000596
Gnomad EAS exome
AF:
0.0373
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00310
GnomAD4 exome
AF:
0.00222
AC:
3247
AN:
1461592
Hom.:
79
Cov.:
30
AF XY:
0.00253
AC XY:
1843
AN XY:
727108
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
AC:
5
AN:
33472
Gnomad4 AMR exome
AF:
0.0000671
AC:
3
AN:
44724
Gnomad4 ASJ exome
AF:
0.000612
AC:
16
AN:
26136
Gnomad4 EAS exome
AF:
0.0475
AC:
1885
AN:
39686
Gnomad4 SAS exome
AF:
0.0123
AC:
1060
AN:
86246
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53420
Gnomad4 NFE exome
AF:
0.0000414
AC:
46
AN:
1111762
Gnomad4 Remaining exome
AF:
0.00379
AC:
229
AN:
60380
Heterozygous variant carriers
0
195
391
586
782
977
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
46
92
138
184
230
<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:
0.00220
AC:
335
AN:
152250
Hom.:
7
Cov.:
32
AF XY:
0.00249
AC XY:
185
AN XY:
74426
show subpopulations
Gnomad4 AFR
AF:
0.000193
AC:
0.000192558
AN:
0.000192558
Gnomad4 AMR
AF:
0.000131
AC:
0.000130736
AN:
0.000130736
Gnomad4 ASJ
AF:
0.000864
AC:
0.000864055
AN:
0.000864055
Gnomad4 EAS
AF:
0.0465
AC:
0.0465251
AN:
0.0465251
Gnomad4 SAS
AF:
0.0143
AC:
0.0143451
AN:
0.0143451
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.0000441
AC:
0.0000441021
AN:
0.0000441021
Gnomad4 OTH
AF:
0.00425
AC:
0.00425331
AN:
0.00425331
Heterozygous variant carriers
0
16
32
47
63
79
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00131
Hom.:
6
Bravo
AF:
0.00174
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00422
AC:
513
Asia WGS
AF:
0.0250
AC:
88
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

Primary ciliary dyskinesia Benign:3
Jun 02, 2015
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This 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. -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 20, 2020
Natera, Inc.
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Primary ciliary dyskinesia 3 Benign:3
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance:Likely benign
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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Nov 30, 2021
Fulgent Genetics, Fulgent Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 06, 2017
Counsyl
Significance:Likely benign
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. -

not provided Benign:2
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

May 05, 2021
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.48
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.28
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.47
T
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
1.0
D
MetaRNN
Benign
0.012
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Pathogenic
3.5
H
PrimateAI
Uncertain
0.54
T
PROVEAN
Pathogenic
-6.4
D
REVEL
Uncertain
0.32
Sift
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.66
MVP
0.59
MPC
0.45
ClinPred
0.15
T
GERP RS
3.8
Varity_R
0.84
gMVP
0.82
Mutation Taster
=84/16
polymorphism

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: rs3756672; hg19: chr5-13719018; COSMIC: COSV99447099; API