rs201077964

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001369.3(DNAH5):​c.962C>T​(p.Ser321Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000486 in 1,613,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. S321S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00050 ( 0 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

8
7
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:1

Conservation

PhyloP100: 9.88
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: Uncertain_significance. The variant received 2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAH5NM_001369.3 linkc.962C>T p.Ser321Leu missense_variant Exon 7 of 79 ENST00000265104.5 NP_001360.1 Q8TE73

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAH5ENST00000265104.5 linkc.962C>T p.Ser321Leu missense_variant Exon 7 of 79 1 NM_001369.3 ENSP00000265104.4 Q8TE73

Frequencies

GnomAD3 genomes
AF:
0.000375
AC:
57
AN:
152012
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000524
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000647
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.000315
AC:
79
AN:
251036
AF XY:
0.000339
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000173
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000218
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000573
Gnomad OTH exome
AF:
0.000326
GnomAD4 exome
AF:
0.000498
AC:
728
AN:
1461644
Hom.:
0
Cov.:
32
AF XY:
0.000488
AC XY:
355
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
AC:
2
AN:
33472
Gnomad4 AMR exome
AF:
0.000134
AC:
6
AN:
44718
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26130
Gnomad4 EAS exome
AF:
0.0000756
AC:
3
AN:
39694
Gnomad4 SAS exome
AF:
0.00
AC:
0
AN:
86236
Gnomad4 FIN exome
AF:
0.000150
AC:
8
AN:
53420
Gnomad4 NFE exome
AF:
0.000622
AC:
692
AN:
1111840
Gnomad4 Remaining exome
AF:
0.000282
AC:
17
AN:
60372
Heterozygous variant carriers
0
41
82
122
163
204
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Variant carriers
0
22
44
66
88
110
<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:
0.000375
AC:
57
AN:
152012
Hom.:
0
Cov.:
32
AF XY:
0.000350
AC XY:
26
AN XY:
74226
show subpopulations
Gnomad4 AFR
AF:
0.0000483
AC:
0.0000483465
AN:
0.0000483465
Gnomad4 AMR
AF:
0.000524
AC:
0.000524315
AN:
0.000524315
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 FIN
AF:
0.000189
AC:
0.000188929
AN:
0.000188929
Gnomad4 NFE
AF:
0.000647
AC:
0.000647097
AN:
0.000647097
Gnomad4 OTH
AF:
0.000478
AC:
0.000478469
AN:
0.000478469
Heterozygous variant carriers
0
3
6
8
11
14
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000419
Hom.:
0
Bravo
AF:
0.000272
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000305
AC:
37
EpiCase
AF:
0.000218
EpiControl
AF:
0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 3 Pathogenic:1Uncertain:2
Oct 03, 2022
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:research

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Sep 18, 2017
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Primary ciliary dyskinesia Uncertain:2Benign:1
Apr 20, 2018
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.S321L variant (also known as c.962C>T), located in coding exon 7 of the DNAH5 gene, results from a C to T substitution at nucleotide position 962. The serine at codon 321 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Oct 28, 2019
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Oct 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Dec 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.036
T
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.69
D
Eigen
Pathogenic
0.97
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Uncertain
0.13
D
MutationAssessor
Pathogenic
3.7
H
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-5.5
D
REVEL
Uncertain
0.61
Sift
Uncertain
0.0010
D
Polyphen
1.0
D
Vest4
0.91
MVP
0.88
MPC
0.30
ClinPred
0.75
D
GERP RS
5.5
Varity_R
0.91
gMVP
0.76
Mutation Taster
=36/64
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs201077964; hg19: chr5-13919298; COSMIC: COSV99451669; API