rs587776953
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001305581.2(LRMDA):c.150dupC(p.Ala51ArgfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001305581.2 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
LRMDA | NM_001305581.2 | c.150dupC | p.Ala51ArgfsTer39 | frameshift_variant | Exon 3 of 7 | ENST00000611255.5 | NP_001292510.1 | |
LRMDA | NM_032024.5 | c.66dupC | p.Ala23ArgfsTer39 | frameshift_variant | Exon 2 of 6 | NP_114413.1 | ||
LRMDA | NR_131178.2 | n.504dupC | non_coding_transcript_exon_variant | Exon 4 of 8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
LRMDA | ENST00000611255.5 | c.150dupC | p.Ala51ArgfsTer39 | frameshift_variant | Exon 3 of 7 | 5 | NM_001305581.2 | ENSP00000480240.1 | ||
LRMDA | ENST00000372499.5 | c.66dupC | p.Ala23ArgfsTer39 | frameshift_variant | Exon 2 of 6 | 1 | ENSP00000361577.1 | |||
LRMDA | ENST00000593699.5 | n.504dupC | non_coding_transcript_exon_variant | Exon 4 of 8 | 1 | |||||
LRMDA | ENST00000593817.1 | n.111dupC | non_coding_transcript_exon_variant | Exon 2 of 2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.000191 AC: 29AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251300Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135812
GnomAD4 exome AF: 0.000280 AC: 409AN: 1461828Hom.: 0 Cov.: 32 AF XY: 0.000254 AC XY: 185AN XY: 727212
GnomAD4 genome AF: 0.000191 AC: 29AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74334
ClinVar
Submissions by phenotype
Oculocutaneous albinism type 7 Pathogenic:2
The LRMDA c.66dup; p.Ala23ArgfsTer39 variant (rs587776953) is reported in the literature in several affected homozygous individuals (Bataille 2020, Gronskov 2013, Lasseaux 2018). This variant is also reported in ClinVar (Variation ID: 41917). This variant is found in the general population with an overall allele frequency of 0.007% (19/282,690 alleles) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Bataille P et al. Clinical variability and probable founder effect in oculocutaneous albinism type 7. Clin Genet. 2020 Mar;97(3):527-528. PMID: 31694064. Gronskov K et al. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism. Am J Hum Genet. 2013 Mar 7;92(3):415-21. PMID: 23395477. Lasseaux E et al. Molecular characterization of a series of 990 index patients with albinism. Pigment Cell Melanoma Res. 2018 Jul;31(4):466-474. PMID: 29345414. -
- -
not provided Pathogenic:2
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29345414, 31980526, 31694064, 23395477) -
This sequence change creates a premature translational stop signal (p.Ala23Argfs*39) in the C10orf11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C10orf11 are known to be pathogenic (PMID: 23395477, 29345414). This variant is present in population databases (rs758262905, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with oculocutaneous albinism (PMID: 23395477, 31694064). This variant is also known as c.150dupC. ClinVar contains an entry for this variant (Variation ID: 41917). For these reasons, this variant has been classified as Pathogenic. -
LRMDA-related disorder Pathogenic:1
The LRMDA c.66dupC variant is predicted to result in a frameshift and premature protein termination (p.Ala23Argfs*39). This variant has been reported in the homozygous state in individuals with autosomal recessive oculocutaneous albinism (Grønskov et al. 2013. PubMed ID: 23395477; Supplemental Table, Holtan et al. 2019. PubMed ID: 31429209; Bataille et al. 2020. PubMed ID: 31694064). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in LRMDA are expected to be pathogenic. We interpret this variant as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at