rs533107744
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_001206927.2(DNAH8):c.11902G>A(p.Gly3968Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
DNAH8
NM_001206927.2 missense
NM_001206927.2 missense
Scores
2
9
4
Clinical Significance
Conservation
PhyloP100: 9.92
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.826
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH8 | NM_001206927.2 | c.11902G>A | p.Gly3968Ser | missense_variant | 79/93 | ENST00000327475.11 | |
DNAH8-AS1 | NR_038401.1 | n.61-2491C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH8 | ENST00000327475.11 | c.11902G>A | p.Gly3968Ser | missense_variant | 79/93 | 5 | NM_001206927.2 | P2 | |
DNAH8-AS1 | ENST00000416948.1 | n.53-2491C>T | intron_variant, non_coding_transcript_variant | 2 | |||||
DNAH8 | ENST00000359357.7 | c.11251G>A | p.Gly3751Ser | missense_variant | 77/91 | 2 | A2 | ||
DNAH8 | ENST00000449981.6 | c.11902G>A | p.Gly3968Ser | missense_variant | 78/82 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152122Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251196Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135762
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460914Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726806
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GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74448
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2022 | The c.11902G>A (p.G3968S) alteration is located in exon 79 (coding exon 78) of the DNAH8 gene. This alteration results from a G to A substitution at nucleotide position 11902, causing the glycine (G) at amino acid position 3968 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces glycine with serine at codon 3968 of the DNAH8 protein (p.Gly3968Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs533107744, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
REVEL
Uncertain
Polyphen
1.0
.;.;D
Vest4
MutPred
0.77
.;.;Loss of catalytic residue at L3752 (P = 0.1806);
MVP
MPC
0.58
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at