rs376160270
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_133642.5(LARGE1):c.1413C>A(p.Ser471Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. S471G) has been classified as Uncertain significance.
Frequency
Consequence
NM_133642.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LARGE1 | NM_133642.5 | c.1413C>A | p.Ser471Arg | missense_variant | 11/15 | ENST00000397394.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LARGE1 | ENST00000397394.8 | c.1413C>A | p.Ser471Arg | missense_variant | 11/15 | 5 | NM_133642.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000319 AC: 8AN: 251136Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135732
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461776Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 727192
GnomAD4 genome ? AF: 0.0000394 AC: 6AN: 152294Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74462
ClinVar
Submissions by phenotype
Muscular dystrophy-dystroglycanopathy type B6 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 471 of the LARGE1 protein (p.Ser471Arg). This variant is present in population databases (rs376160270, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of LARGE1-related conditions (PMID: 28454995). ClinVar contains an entry for this variant (Variation ID: 579774). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LARGE1 protein function with a negative predictive value of 80%. 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. - |
Muscular dystrophy-dystroglycanopathy type B6;C3150414:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A6;C4284790:Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2022 | Reported as heterozygous along with a likely benign variant in LARGE1 in a patient with muscular dystrophy; information about segregation analysis was not provided (Alfares et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28454995, 34426522, 25279699, 24709677) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at