chr7-21635979-A-G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_001277115.2(DNAH11):​c.4609A>G​(p.Met1537Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,630 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1537I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 1 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

2
15

Clinical Significance

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

Conservation

PhyloP100: 1.46

Publications

0 publications found
Variant links:
Genes affected
DNAH11 (HGNC:2942): (dynein axonemal heavy chain 11) This gene encodes a ciliary outer dynein arm protein and is a member of the dynein heavy chain family. It is a microtubule-dependent motor ATPase and has been reported to be involved in the movement of respiratory cilia. Mutations in this gene have been implicated in causing Kartagener Syndrome (a combination of situs inversus totalis and Primary Ciliary Dyskinesia (PCD), also called Immotile Cilia Syndrome 1 (ICS1)) and male sterility. [provided by RefSeq, Mar 2013]
DNAH11 Gene-Disease associations (from GenCC):
  • primary ciliary dyskinesia 7
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
  • primary ciliary dyskinesia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.19920549).
BP6
Variant 7-21635979-A-G is Benign according to our data. Variant chr7-21635979-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 575632.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAH11NM_001277115.2 linkc.4609A>G p.Met1537Val missense_variant Exon 26 of 82 ENST00000409508.8 NP_001264044.1 Q96DT5Q96NT7H9NAJ8H9NAJ7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAH11ENST00000409508.8 linkc.4609A>G p.Met1537Val missense_variant Exon 26 of 82 5 NM_001277115.2 ENSP00000475939.1 Q96DT5
DNAH11ENST00000465593.1 linkn.635A>G non_coding_transcript_exon_variant Exon 4 of 4 2

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152242
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000161
AC:
4
AN:
248332
AF XY:
0.00000742
show subpopulations
Gnomad AFR exome
AF:
0.000130
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000889
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461388
Hom.:
1
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
726934
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44696
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26124
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39680
South Asian (SAS)
AF:
0.0000697
AC:
6
AN:
86136
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53398
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111746
Other (OTH)
AF:
0.00
AC:
0
AN:
60362
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.455
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Hom
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
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152242
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74374
show subpopulations
African (AFR)
AF:
0.0000482
AC:
2
AN:
41464
American (AMR)
AF:
0.00
AC:
0
AN:
15280
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5200
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68048
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.592
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

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:
0.0000508
Hom.:
0
Bravo
AF:
0.0000453
ESP6500AA
AF:
0.000534
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

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

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1Benign:1
Oct 17, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 05, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.4609A>G (p.M1537V) alteration is located in exon 26 (coding exon 26) of the DNAH11 gene. This alteration results from a A to G substitution at nucleotide position 4609, causing the methionine (M) at amino acid position 1537 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.24
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
18
DANN
Benign
0.85
DEOGEN2
Benign
0.19
.;.;T
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.26
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Benign
0.0099
T
MetaRNN
Benign
0.20
T;T;T
MetaSVM
Benign
-0.93
T
PhyloP100
1.5
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-1.7
.;N;.
REVEL
Benign
0.077
Sift
Benign
0.032
.;D;.
Vest4
0.52
MVP
0.39
ClinPred
0.035
T
GERP RS
4.4
Varity_R
0.27
gMVP
0.37
Mutation Taster
=81/19
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

Other links and lift over

dbSNP: rs371095430; hg19: chr7-21675597; API