NM_003640.5:c.3785C>T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_003640.5(ELP1):c.3785C>T(p.Thr1262Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_003640.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ELP1 | NM_003640.5 | c.3785C>T | p.Thr1262Met | missense_variant | Exon 35 of 37 | ENST00000374647.10 | NP_003631.2 | |
ELP1 | NM_001318360.2 | c.3443C>T | p.Thr1148Met | missense_variant | Exon 35 of 37 | NP_001305289.1 | ||
ELP1 | NM_001330749.2 | c.2738C>T | p.Thr913Met | missense_variant | Exon 33 of 35 | NP_001317678.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152148Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251460Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135904
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461576Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 30AN XY: 727130
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74318
ClinVar
Submissions by phenotype
not provided Uncertain:3
The p.Thr1262Met variant (rs199723919) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.03 percent in the European Finnish population (identified on 8 out of 25,790 chromosomes), and has been reported to the ClinVar database (Variation ID: 364554). The threonine at position 1262 is weakly conserved considering 13 species (Alamut v2.11) and computational analyses of the p.Thr1262Met variant on protein structure and function indicate a neutral effect (SIFT: tolerated, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Thr1262Met variant with certainty. -
In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1262 of the ELP1 protein (p.Thr1262Met). This variant is present in population databases (rs199723919, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with ELP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 364554). 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 methionine 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. -
Familial dysautonomia Uncertain:2
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
not specified Uncertain:1
The c.3785C>T (p.T1262M) alteration is located in exon 35 (coding exon 34) of the IKBKAP gene. This alteration results from a C to T substitution at nucleotide position 3785, causing the threonine (T) at amino acid position 1262 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Familial dysautonomia;C0025149:Medulloblastoma Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at