9-34500823-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_012144.4(DNAI1):c.1003G>T(p.Val335Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,678 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V335I) has been classified as Benign.
Frequency
Consequence
NM_012144.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNAI1 | NM_012144.4 | c.1003G>T | p.Val335Phe | missense_variant | 11/20 | ENST00000242317.9 | NP_036276.1 | |
DNAI1 | NM_001281428.2 | c.1015G>T | p.Val339Phe | missense_variant | 11/20 | NP_001268357.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DNAI1 | ENST00000242317.9 | c.1003G>T | p.Val335Phe | missense_variant | 11/20 | 1 | NM_012144.4 | ENSP00000242317.4 | ||
DNAI1 | ENST00000614641.4 | c.1015G>T | p.Val339Phe | missense_variant | 11/20 | 5 | ENSP00000480538.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251262Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135800
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461678Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727160
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Kartagener syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Jul 19, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 05, 2024 | Variant summary: DNAI1 c.1003G>T (p.Val335Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251262 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1003G>T has been reported in the literature as compound heterozygous genotype in an individual affected with clinical features of Kartagener syndrome (Westphal_2019). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30868567). ClinVar contains an entry for this variant (Variation ID: 525451). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 07, 2021 | This sequence change replaces valine with phenylalanine at codon 335 of the DNAI1 protein (p.Val335Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is present in population databases (rs11793196, ExAC 0.002%). This missense change has been observed in individual(s) with clinical features of DNAI1-related conditions (PMID: 30868567). 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: "Possibly Damaging"; 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at