rs776744908

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001206927.2(DNAH8):​c.142T>C​(p.Ser48Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000138 in 1,612,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

DNAH8
NM_001206927.2 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -1.08
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.04782507).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAH8NM_001206927.2 linkc.142T>C p.Ser48Pro missense_variant Exon 2 of 93 ENST00000327475.11 NP_001193856.1 Q96JB1Q8IU65A0A075B6F3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAH8ENST00000327475.11 linkc.142T>C p.Ser48Pro missense_variant Exon 2 of 93 5 NM_001206927.2 ENSP00000333363.7 A0A075B6F3
DNAH8ENST00000373278.8 linkc.142T>C p.Ser48Pro missense_variant Exon 2 of 5 1 ENSP00000362375.4 Q8IU65
DNAH8ENST00000449981.6 linkc.142T>C p.Ser48Pro missense_variant Exon 1 of 82 5 ENSP00000415331.2 H0Y7V4
DNAH8ENST00000359357.7 linkc.-425T>C upstream_gene_variant 2 ENSP00000352312.3 Q96JB1-1

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152154
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.000176
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000140
AC:
34
AN:
243198
Hom.:
0
AF XY:
0.000157
AC XY:
21
AN XY:
133428
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000132
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000220
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.000143
AC:
209
AN:
1460404
Hom.:
0
Cov.:
32
AF XY:
0.000145
AC XY:
105
AN XY:
726494
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000166
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152154
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000184
Hom.:
0
Bravo
AF:
0.000151
ExAC
AF:
0.000173
AC:
20
EpiCase
AF:
0.000218
EpiControl
AF:
0.000296

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:2
Mar 30, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BP4_strong -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Primary ciliary dyskinesia Uncertain:1
Dec 27, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 48 of the DNAH8 protein (p.Ser48Pro). This variant is present in population databases (rs776744908, gnomAD 0.02%). 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: 525258). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
BayesDel_addAF
Benign
-0.56
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
0.083
DANN
Benign
0.93
DEOGEN2
Benign
0.010
T;.;T
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.6
FATHMM_MKL
Benign
0.016
N
LIST_S2
Benign
0.31
T;T;T
M_CAP
Benign
0.0024
T
MetaRNN
Benign
0.048
T;T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.37
T
PROVEAN
Benign
0.070
.;N;N
REVEL
Benign
0.026
Sift
Benign
0.12
.;T;T
Sift4G
Uncertain
0.043
.;D;.
Polyphen
0.0
.;B;.
Vest4
0.12
MVP
0.072
ClinPred
0.15
T
GERP RS
-4.6
gMVP
0.090

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776744908; hg19: chr6-38690727; API