rs199779645
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001206927.2(DNAH8):c.9025C>A(p.Leu3009Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000089 in 1,584,744 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000091 ( 0 hom. )
Consequence
DNAH8
NM_001206927.2 missense
NM_001206927.2 missense
Scores
5
10
Clinical Significance
Conservation
PhyloP100: 0.220
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH8 | NM_001206927.2 | c.9025C>A | p.Leu3009Met | missense_variant | 61/93 | ENST00000327475.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH8 | ENST00000327475.11 | c.9025C>A | p.Leu3009Met | missense_variant | 61/93 | 5 | NM_001206927.2 | P2 | |
DNAH8 | ENST00000359357.7 | c.8374C>A | p.Leu2792Met | missense_variant | 59/91 | 2 | A2 | ||
DNAH8 | ENST00000449981.6 | c.9025C>A | p.Leu3009Met | missense_variant | 60/82 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152118Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000490 AC: 11AN: 224318Hom.: 0 AF XY: 0.0000658 AC XY: 8AN XY: 121648
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GnomAD4 exome AF: 0.0000914 AC: 131AN: 1432626Hom.: 0 Cov.: 29 AF XY: 0.0000871 AC XY: 62AN XY: 711638
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GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152118Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74294
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
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 | Sep 01, 2021 | The c.9025C>A (p.L3009M) alteration is located in exon 61 (coding exon 60) of the DNAH8 gene. This alteration results from a C to A substitution at nucleotide position 9025, causing the leucine (L) at amino acid position 3009 to be replaced by a methionine (M). 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 | Aug 26, 2021 | This sequence change replaces leucine with methionine at codon 3009 of the DNAH8 protein (p.Leu3009Met). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and methionine. This variant is present in population databases (rs199779645, ExAC 0.01%). 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 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"). 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. - |
Spermatogenic failure 46 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 01, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
REVEL
Benign
Polyphen
0.95
.;.;P
Vest4
MVP
MPC
0.52
ClinPred
T
GERP RS
Varity_R
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