rs1131692250
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_015512.5(DNAH1):c.8626-1G>A variant causes a splice acceptor change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).
Frequency
Genomes: not found (cov: 33)
Consequence
DNAH1
NM_015512.5 splice_acceptor
NM_015512.5 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.98
Genes affected
DNAH1 (HGNC:2940): (dynein axonemal heavy chain 1) This gene encodes an inner dynein arm heavy chain that provides structural support between the radial spokes and the outer doublet of the sperm tail. Naturally occurring mutations in this gene are associated with primary ciliary dyskinesia and multiple morphological anomalies of the flagella that result in asthenozoospermia and male infertility. Mice with a homozygous knockout of the orthologous gene are viable but have reduced sperm motility and are infertile. [provided by RefSeq, Feb 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.014455384 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of 1, new splice context is: ctatgtctcccatccccaAGtgg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-52386159-G-A is Pathogenic according to our data. Variant chr3-52386159-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 430857.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-52386159-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNAH1 | NM_015512.5 | c.8626-1G>A | splice_acceptor_variant | ENST00000420323.7 | NP_056327.4 | |||
DNAH1 | XM_017006129.2 | c.8695-1G>A | splice_acceptor_variant | XP_016861618.1 | ||||
DNAH1 | XM_017006130.2 | c.8626-1G>A | splice_acceptor_variant | XP_016861619.1 | ||||
DNAH1 | XM_017006131.2 | c.8695-1G>A | splice_acceptor_variant | XP_016861620.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DNAH1 | ENST00000420323.7 | c.8626-1G>A | splice_acceptor_variant | 1 | NM_015512.5 | ENSP00000401514 | P1 | |||
DNAH1 | ENST00000486752.5 | n.8887-1G>A | splice_acceptor_variant, non_coding_transcript_variant | 2 | ||||||
DNAH1 | ENST00000488988.5 | n.216-1G>A | splice_acceptor_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Spermatogenic failure 18 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 20, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 2
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at