9-34500844-G-C
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_012144.4(DNAI1):c.1019+5G>C variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.00000621 in 1,611,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
DNAI1
NM_012144.4 splice_donor_5th_base, intron
NM_012144.4 splice_donor_5th_base, intron
Scores
2
Splicing: ADA: 0.9951
2
Clinical Significance
Conservation
PhyloP100: 6.34
Genes affected
DNAI1 (HGNC:2954): (dynein axonemal intermediate chain 1) This gene encodes a member of the dynein intermediate chain family. The encoded protein is part of the dynein complex in respiratory cilia. The inner- and outer-arm dyneins, which bridge between the doublet microtubules in axonemes, are the force-generating proteins responsible for the sliding movement in axonemes. The intermediate and light chains, thought to form the base of the dynein arm, help mediate attachment and may also participate in regulating dynein activity. Mutations in this gene result in abnormal ciliary ultrastructure and function associated with primary ciliary dyskinesia and Kartagener syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 9-34500844-G-C is Pathogenic according to our data. Variant chr9-34500844-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 525418.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAI1 | NM_012144.4 | c.1019+5G>C | splice_donor_5th_base_variant, intron_variant | ENST00000242317.9 | |||
DNAI1 | NM_001281428.2 | c.1031+5G>C | splice_donor_5th_base_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAI1 | ENST00000242317.9 | c.1019+5G>C | splice_donor_5th_base_variant, intron_variant | 1 | NM_012144.4 | ||||
DNAI1 | ENST00000614641.4 | c.1031+5G>C | splice_donor_5th_base_variant, intron_variant | 5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152240Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251362Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135862
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GnomAD4 exome AF: 0.00000617 AC: 9AN: 1459178Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4AN XY: 726058
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change falls in intron 11 of the DNAI1 gene. It does not directly change the encoded amino acid sequence of the DNAI1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs747121305, gnomAD 0.01%). This variant has been observed in individual(s) with DNAI1-related conditions (PMID: 31772028; Invitae). ClinVar contains an entry for this variant (Variation ID: 525418). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
DNAI1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 08, 2023 | The DNAI1 c.1019+5G>C variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous state in two siblings with primary ciliary dyskinesia (reported as c.1031+5G>T in Table 1, Paff. 2018. PubMed ID: 29363216) and found in the homozygous state in four individuals with primary ciliary dyskinesia (Table S3, Blanchon et al 2020. PubMed ID: 31772028). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-34500842-G-C). In summary, this variant is interpreted as likely pathogenic . - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at