rs201250825
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_000117.3(EMD):c.400G>A(p.Val134Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 1,210,488 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V134V) has been classified as Likely benign.
Frequency
Consequence
NM_000117.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EMD | NM_000117.3 | c.400G>A | p.Val134Met | missense_variant, splice_region_variant | 5/6 | ENST00000369842.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EMD | ENST00000369842.9 | c.400G>A | p.Val134Met | missense_variant, splice_region_variant | 5/6 | 1 | NM_000117.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000888 AC: 1AN: 112579Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34745
GnomAD3 exomes AF: 0.00000546 AC: 1AN: 183191Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67861
GnomAD4 exome AF: 0.00000638 AC: 7AN: 1097909Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 2AN XY: 363393
GnomAD4 genome ? AF: 0.00000888 AC: 1AN: 112579Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 34745
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 16, 2019 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function - |
Emery-Dreifuss muscular dystrophy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Emery-Dreifuss muscular dystrophy 1, X-linked Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 31, 2019 | - - |
X-linked Emery-Dreifuss muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 30, 2021 | This sequence change replaces valine with methionine at codon 134 of the EMD protein (p.Val134Met). The valine residue is highly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with EMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 444835). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at