chr1-92263676-CA-C
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS2_Supporting
The NM_053274.3(GLMN):βc.1355delTβ(p.Leu452TrpfsTer24) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000997 in 1,604,588 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_053274.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152088Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251426Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135884
GnomAD4 exome AF: 0.00000964 AC: 14AN: 1452500Hom.: 0 Cov.: 27 AF XY: 0.00000829 AC XY: 6AN XY: 723378
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152088Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74296
ClinVar
Submissions by phenotype
Glomuvenous malformation Pathogenic:2
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The p.Leu425TrpfsX24 variant in GLMN has been reported in one individual with gl omuvenous malformations and segregated with disease in at least 5 affected famil y members (Brouillard 2002). It has also been identified in 0.004% (4/111662) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad. broadinstitute.org). This variant is predicted to cause a frameshift, which alte rs the protein?s amino acid sequence beginning at position 452 and leads to a pr emature termination codon 24 amino acids downstream. This alteration is then pre dicted to lead to a truncated or absent protein. Loss of function of the GLMN ge ne is an established disease mechanism in autosomal dominant glomuvenous malform ation. In summary, although additional studies are required to fully establish i ts clinical significance, the p.Leu425TrpfsX24 variant is likely pathogenic. ACM G/AMP Criteria applied: PVS1, PP1_Moderate. -
GLMN-related disorder Pathogenic:1
The GLMN c.1355delT variant is predicted to result in a frameshift and premature protein termination (p.Leu452Trpfs*24). This variant was reported in one family with 6 affected individuals with glomuvenous malformations (Brouillard et al 2002. PubMed ID: 11845407). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/). Frameshift variants in GLMN are expected to be pathogenic. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at