rs149938578
Positions:
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_001206927.2(DNAH8):āc.13954T>Cā(p.Phe4652Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000085 ( 0 hom., cov: 32)
Exomes š: 0.000031 ( 0 hom. )
Consequence
DNAH8
NM_001206927.2 missense
NM_001206927.2 missense
Scores
2
3
10
Clinical Significance
Conservation
PhyloP100: 7.57
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 Likely_benign. Variant got -1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.23528033).
BS1
?
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000308 (45/1461884) while in subpopulation AFR AF= 0.00111 (37/33480). AF 95% confidence interval is 0.000824. There are 0 homozygotes in gnomad4_exome. There are 25 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH8 | NM_001206927.2 | c.13954T>C | p.Phe4652Leu | missense_variant | 93/93 | ENST00000327475.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH8 | ENST00000327475.11 | c.13954T>C | p.Phe4652Leu | missense_variant | 93/93 | 5 | NM_001206927.2 | P2 | |
DNAH8 | ENST00000359357.7 | c.13303T>C | p.Phe4435Leu | missense_variant | 91/91 | 2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000855 AC: 13AN: 152120Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251430Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135878
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GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25AN XY: 727244
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GnomAD4 genome ? AF: 0.0000855 AC: 13AN: 152120Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74308
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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 | Dec 30, 2023 | The c.13954T>C (p.F4652L) alteration is located in exon 93 (coding exon 92) of the DNAH8 gene. This alteration results from a T to C substitution at nucleotide position 13954, causing the phenylalanine (F) at amino acid position 4652 to be replaced by a leucine (L). 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 16, 2022 | This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 4652 of the DNAH8 protein (p.Phe4652Leu). This variant is present in population databases (rs149938578, gnomAD 0.05%). 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: 525332). 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. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
REVEL
Benign
Polyphen
0.019
.;B
Vest4
MutPred
0.46
.;Loss of sheet (P = 0.1501);
MVP
MPC
0.24
ClinPred
T
GERP RS
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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