NM_001206927.2:c.2159A>T

Variant summary

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

The NM_001206927.2(DNAH8):​c.2159A>T​(p.Asp720Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

1
6
11

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.92

Publications

0 publications found
Variant links:
Genes affected
DNAH8 (HGNC:2952): (dynein axonemal heavy chain 8) The protein encoded by this gene is a heavy chain of an axonemal dynein involved in sperm and respiratory cilia motility. Axonemal dyneins generate force through hydrolysis of ATP and binding to microtubules. [provided by RefSeq, Jan 2012]
DNAH8 Gene-Disease associations (from GenCC):
  • spermatogenic failure 46
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
  • spermatogenic failure 5
    Inheritance: AR Classification: MODERATE Submitted by: Franklin by Genoox
  • primary ciliary dyskinesia
    Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAH8NM_001206927.2 linkc.2159A>T p.Asp720Val missense_variant Exon 16 of 93 ENST00000327475.11 NP_001193856.1 Q96JB1Q8IU65A0A075B6F3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAH8ENST00000327475.11 linkc.2159A>T p.Asp720Val missense_variant Exon 16 of 93 5 NM_001206927.2 ENSP00000333363.7 A0A075B6F3
DNAH8ENST00000359357.7 linkc.1508A>T p.Asp503Val missense_variant Exon 14 of 91 2 ENSP00000352312.3 Q96JB1-1
DNAH8ENST00000449981.6 linkc.2159A>T p.Asp720Val missense_variant Exon 15 of 82 5 ENSP00000415331.2 H0Y7V4

Frequencies

GnomAD3 genomes
AF:
0.000131
AC:
20
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000483
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000398
AC:
10
AN:
251164
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.000431
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000889
AC:
13
AN:
1461606
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727108
show subpopulations
African (AFR)
AF:
0.000209
AC:
7
AN:
33476
American (AMR)
AF:
0.0000671
AC:
3
AN:
44716
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26124
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39656
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86224
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111852
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60378
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome 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
GnomAD4 genome
AF:
0.000131
AC:
20
AN:
152188
Hom.:
0
Cov.:
32
AF XY:
0.000202
AC XY:
15
AN XY:
74346
show subpopulations
African (AFR)
AF:
0.000483
AC:
20
AN:
41450
American (AMR)
AF:
0.00
AC:
0
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5204
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.530
Heterozygous variant carriers
0
1
2
3
4
5
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:
0.000142
Hom.:
0
Bravo
AF:
0.000117
ESP6500AA
AF:
0.000908
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000741
AC:
9
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 02, 2025
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.2159A>T (p.D720V) alteration is located in exon 16 (coding exon 15) of the DNAH8 gene. This alteration results from a A to T substitution at nucleotide position 2159, causing the aspartic acid (D) at amino acid position 720 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia Uncertain:1
Jun 04, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 720 of the DNAH8 protein (p.Asp720Val). This variant is present in population databases (rs138373981, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. ClinVar contains an entry for this variant (Variation ID: 525380). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.11
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Benign
0.066
T;T;T
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.47
T;T;T
M_CAP
Benign
0.021
T
MetaRNN
Uncertain
0.52
D;D;D
MetaSVM
Benign
-0.85
T
MutationAssessor
Uncertain
2.1
.;.;M
PhyloP100
6.9
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-2.7
.;D;D
REVEL
Benign
0.25
Sift
Benign
0.19
.;T;T
Polyphen
0.90
.;.;P
Vest4
0.72
MVP
0.82
MPC
0.23
ClinPred
0.13
T
GERP RS
5.6
Varity_R
0.62
gMVP
0.49
Mutation Taster
=76/24
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.24
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.24
Position offset: -19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs138373981; hg19: chr6-38749049; API