chr6-38909677-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001206927.2(DNAH8):​c.9673C>A​(p.Gln3225Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000945 in 1,614,082 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00098 ( 3 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

18

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.18

Publications

4 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-AS1 (HGNC:40188): (DNAH8 antisense RNA 1)

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=0.020689428).
BP6
Variant 6-38909677-C-A is Benign according to our data. Variant chr6-38909677-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 454610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000657 (100/152272) while in subpopulation SAS AF = 0.00145 (7/4818). AF 95% confidence interval is 0.000875. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAH8NM_001206927.2 linkc.9673C>A p.Gln3225Lys missense_variant Exon 65 of 93 ENST00000327475.11 NP_001193856.1 Q96JB1Q8IU65A0A075B6F3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAH8ENST00000327475.11 linkc.9673C>A p.Gln3225Lys missense_variant Exon 65 of 93 5 NM_001206927.2 ENSP00000333363.7 A0A075B6F3
DNAH8ENST00000359357.7 linkc.9022C>A p.Gln3008Lys missense_variant Exon 63 of 91 2 ENSP00000352312.3 Q96JB1-1
DNAH8ENST00000449981.6 linkc.9673C>A p.Gln3225Lys missense_variant Exon 64 of 82 5 ENSP00000415331.2 H0Y7V4

Frequencies

GnomAD3 genomes
AF:
0.000657
AC:
100
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00107
Gnomad OTH
AF:
0.00144
GnomAD2 exomes
AF:
0.000892
AC:
224
AN:
251158
AF XY:
0.000958
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000405
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000462
Gnomad NFE exome
AF:
0.00135
Gnomad OTH exome
AF:
0.00196
GnomAD4 exome
AF:
0.000976
AC:
1426
AN:
1461810
Hom.:
3
Cov.:
31
AF XY:
0.00101
AC XY:
736
AN XY:
727220
show subpopulations
African (AFR)
AF:
0.000179
AC:
6
AN:
33478
American (AMR)
AF:
0.000514
AC:
23
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39690
South Asian (SAS)
AF:
0.000927
AC:
80
AN:
86258
European-Finnish (FIN)
AF:
0.000562
AC:
30
AN:
53414
Middle Eastern (MID)
AF:
0.00329
AC:
19
AN:
5768
European-Non Finnish (NFE)
AF:
0.00109
AC:
1211
AN:
1111958
Other (OTH)
AF:
0.000944
AC:
57
AN:
60386
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.462
Heterozygous variant carriers
0
77
153
230
306
383
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
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:
0.000657
AC:
100
AN:
152272
Hom.:
0
Cov.:
32
AF XY:
0.000712
AC XY:
53
AN XY:
74460
show subpopulations
African (AFR)
AF:
0.000192
AC:
8
AN:
41564
American (AMR)
AF:
0.000196
AC:
3
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5192
South Asian (SAS)
AF:
0.00145
AC:
7
AN:
4818
European-Finnish (FIN)
AF:
0.000283
AC:
3
AN:
10608
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.00107
AC:
73
AN:
68016
Other (OTH)
AF:
0.00142
AC:
3
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
5
10
15
20
25
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:
0.00100
Hom.:
0
Bravo
AF:
0.000688
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00128
AC:
11
ExAC
AF:
0.000857
AC:
104
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00120
EpiControl
AF:
0.00160

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Benign:1
Nov 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

DNAH8-related disorder Benign:1
Aug 30, 2023
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.078
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
20
DANN
Benign
0.96
DEOGEN2
Benign
0.023
T;T;T
Eigen
Benign
-0.39
Eigen_PC
Benign
-0.20
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.61
T;T;T
M_CAP
Benign
0.0050
T
MetaRNN
Benign
0.021
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.36
.;.;N
PhyloP100
1.2
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.5
.;N;N
REVEL
Benign
0.072
Sift
Benign
0.14
.;T;T
Polyphen
0.0010
.;.;B
Vest4
0.47
MVP
0.54
MPC
0.16
ClinPred
0.024
T
GERP RS
5.6
Varity_R
0.21
gMVP
0.52
Mutation Taster
=99/1
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: rs138703233; hg19: chr6-38877453; API