NM_001206927.2:c.10690C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001206927.2(DNAH8):​c.10690C>T​(p.Arg3564Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

4
12
2

Clinical Significance

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

Conservation

PhyloP100: 1.86
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-AS1 (HGNC:40188): (DNAH8 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAH8NM_001206927.2 linkc.10690C>T p.Arg3564Trp missense_variant Exon 72 of 93 ENST00000327475.11 NP_001193856.1 Q96JB1Q8IU65A0A075B6F3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAH8ENST00000327475.11 linkc.10690C>T p.Arg3564Trp missense_variant Exon 72 of 93 5 NM_001206927.2 ENSP00000333363.7 A0A075B6F3

Frequencies

GnomAD3 genomes
AF:
0.0000921
AC:
14
AN:
152034
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000720
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
250582
Hom.:
0
AF XY:
0.0000369
AC XY:
5
AN XY:
135436
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1461186
Hom.:
0
Cov.:
30
AF XY:
0.0000138
AC XY:
10
AN XY:
726900
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000921
AC:
14
AN:
152034
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74242
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000720
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.000132
Hom.:
0
Bravo
AF:
0.000128
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 27, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.10690C>T (p.R3564W) alteration is located in exon 72 (coding exon 71) of the DNAH8 gene. This alteration results from a C to T substitution at nucleotide position 10690, causing the arginine (R) at amino acid position 3564 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia Uncertain:1
Mar 03, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. 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"). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. This variant is present in population databases (rs748121138, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 3564 of the DNAH8 protein (p.Arg3564Trp). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.48
BayesDel_addAF
Uncertain
0.026
T
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.22
T;D;D
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.53
D;D;D
MetaSVM
Uncertain
0.27
D
MutationAssessor
Pathogenic
3.1
.;.;M
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-6.8
.;D;D
REVEL
Pathogenic
0.68
Sift
Uncertain
0.0030
.;D;D
Polyphen
1.0
.;.;D
Vest4
0.39
MVP
0.87
MPC
0.59
ClinPred
0.91
D
GERP RS
4.4
Varity_R
0.62
gMVP
0.48

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs748121138; hg19: chr6-38890861; API