NM_012144.4:c.788T>C
Variant summary
Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong
The NM_012144.4(DNAI1):c.788T>C(p.Met263Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M263L) has been classified as Uncertain significance.
Frequency
Consequence
NM_012144.4 missense
Scores
Clinical Significance
Conservation
Publications
- primary ciliary dyskinesia 1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
- primary ciliary dyskinesiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Likely_benign. The variant received -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DNAI1 | NM_012144.4 | c.788T>C | p.Met263Thr | missense_variant | Exon 9 of 20 | ENST00000242317.9 | NP_036276.1 | |
DNAI1 | NM_001281428.2 | c.800T>C | p.Met267Thr | missense_variant | Exon 9 of 20 | NP_001268357.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 31 show subpopulations
GnomAD2 exomes AF: 0.0000199 AC: 5AN: 251272 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461782Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727196 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152160Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74342 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:3
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This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 263 of the DNAI1 protein (p.Met263Thr). This variant is present in population databases (no rsID available, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with DNAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 525420). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
The c.788T>C (p.M263T) alteration is located in exon 9 (coding exon 9) of the DNAI1 gene. This alteration results from a T to C substitution at nucleotide position 788, causing the methionine (M) at amino acid position 263 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at