NM_053274.3:c.157_161delAAGAA

Variant names:

• chr1-92297407-ATTCTT-A
• rs762515373
• NM_053274.3:c.157_161delAAGAA

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_053274.3(GLMN):​c.157_161delAAGAA​(p.Lys53fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000981 in 1,610,474 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:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: GLMN NM_053274.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 6.73

Genes affected

GLMN (HGNC:14373): (glomulin, FKBP associated protein) This gene encodes a phosphorylated protein that is a member of a Skp1-Cullin-F-box-like complex. The protein is essential for normal development of the vasculature and mutations in this gene have been associated with glomuvenous malformations, also called glomangiomas. Multiple splice variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-92297407-ATTCTT-A is Pathogenic according to our data. Variant chr1-92297407-ATTCTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 7806.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-92297407-ATTCTT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLMN	NM_053274.3	c.157_161delAAGAA	p.Lys53fs	frameshift_variant	Exon 3 of 19	ENST00000370360.8	NP_444504.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLMN	ENST00000370360.8	c.157_161delAAGAA	p.Lys53fs	frameshift_variant	Exon 3 of 19	1	NM_053274.3	ENSP00000359385.3
GLMN	ENST00000495106.5	n.157_161delAAGAA		non_coding_transcript_exon_variant	Exon 3 of 18	1		ENSP00000436829.1
GLMN	ENST00000487911.1	n.*109_*113delAAGAA		downstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151694 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251380 Hom.: 0 AF XY: 0.0000736 AC XY: 10 AN XY: 135848

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000104 AC: 151 AN: 1458780 Hom.: 0 AF XY: 0.000109 AC XY: 79 AN XY: 725948

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151694 Hom.: 0 Cov.: 30 AF XY: 0.0000405 AC XY: 3 AN XY: 74068

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000529

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glomuvenous malformation Pathogenic:8

Jan 16, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glomuvenous malformations (MIM#138000). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (14 heterozygotes, 0 homozygotes). (SP) 0701 - Other variants predicted to result in NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals and is the most common variant in the GLMN gene associated with glomuvenous malformations (ClinVar, PMID: 23801931). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 02, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in GLMN is a frameshift variant predicted to cause a premature stop codon, p.(Lys53*), in biologically relevant exon 3/19 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.02% (6/30,610 alleles) in the South Asian population. This variant is the most commonly reported variant causing glomuvenous malformations (PMID: 23801931), and segregates with disease in multiple families (PMID: 11845407, 30460983). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong. -

Sep 16, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GLMN c.157_161delAAGAA variant (rs762515373) is one of a common variants associated with glomuvenous malformations (Brouillard 2002, Brouillard 2005, Suárez-Magdalena 2019). These reports demonstrated segregation of this variant with disease from over 20 families, and with similar haplotype sharing suggestive of a common ancestral origin. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.02 percent in the South Asian population (identified on 6 out of 30,610 chromosomes) and has been reported to the ClinVar database as pathogenic (Variation ID: 7806). This variant causes a frameshift by deleting 5 nucleotides in the third exon (of 19 total exons), and is predicted to result in a truncated protein. Truncating variants in GLMN are a common mechanism of disease. Based on these observations, the c.157_161del is considered to be pathogenic. Pathogenic variants in GLMN are inherited in an autosomal dominant manner and are associated with glomuvenous malformations (MIM: 138000). Reduced penetrance and phenotypic variability are thought to be accounted for by somatic second hit variants, most commonly uniparental isodisomy involving chromosome 1p (Amyere 2013). References: Amyere et al. Somatic uniparental isodisomy explains multifocality of glomuvenous malformations. Am J Hum Genet. 2013 Feb 7;92(2):188-96. doi: 10.1016/j.ajhg.2012.12.017. Epub 2013 Jan 31. Brouillard et al. Mutations in a novel factor, glomulin, are responsible for glomuvenous malformations ("glomangiomas"). Am J Hum Genet. 2002 Apr;70(4):866-74. Brouillard et al. Four common glomulin mutations cause two thirds of glomuvenous malformations ("familial glomangiomas"): evidence for a founder effect. J Med Genet. 2005 Feb;42(2):e13. Suárez-Magdalena et al., Glomulin gene c.157_161del mutation in a family with multiple glomuvenous malformations. Int J Dermatol. 2019 Feb;58(2):e43-e45. -

Oct 06, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 19, 2024

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PS4, PM2 -

Jun 10, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A GLMN c.157_161del (p.Lys53*) variant was identified at a heterozygous allelic fraction of 50.9%, a frequency which is consistent with germline origin. This variant has been reported in numerous individuals with glomuvenous malformations (Brouillard P et al., PMID: 23801931; Suárez-Magdalena O et al., PMID: 30460983; Brouillard P et al., PMID: 11845407). This variant has been reported in the ClinVar database as a germline pathogenic variant by multiple submitters (ClinVar ID: 7806) and is observed on 158/1,610,474 alleles in the general population (gnomAD v.4.1.0). This variant is a deletion of five nucleotides, which results in a frameshift, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this GLMN c.157_161del (p.Lys53*) variant is classified as pathogenic. -

not provided Pathogenic:2

Dec 09, 2019

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157_161delAAGAA (p.Lys53*) variant is one of the most frequently reported pathogenic GLMN variants, accounting for ~45% of affected individuals (Ref 1-3). The deletion of five nucleotides replaces the lysine with a premature stop codon at position 53 (p.Lys53*). This variant is predicted to result in a loss of gene function. -

Apr 06, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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; This variant is associated with the following publications: (PMID: 30325312, 23801931, 11845407, 30460983, 32538359, 11175297, 31589614) -

Inborn genetic diseases Pathogenic:1

Mar 01, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157_161delAAGAA (p.K53*) alteration, located in exon 3 (coding exon 2) of the GLMN gene, consists of a deletion of 5 nucleotides from position 157 to 161, causing a translational frameshift with a predicted alternate stop codon after amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.005% (14/282026) total alleles studied. The highest observed frequency was 0.02% (6/30610) of South Asian alleles. This variant has been reported in multiple individuals with glomuvenous malformations and has been to show to segregate with the phenotype in multiple large families (Brouillard, 2002; Brouillard, 2013; Su&aacute;rez-Magdalena, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

GLMN-related disorder Pathogenic:1

Jul 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The GLMN c.157_161del5 variant is predicted to result in premature protein termination (p.Lys53*). This variant has been reported to be causative for autosomal dominant glomuvenous malformations in multiple families (referred to as 157delAAGAA - Brouillard et al. 2002. PubMed ID: 11845407). This variant is reported in 0.019% of alleles in individuals of South Asian in gnomAD. Loss-of-function variants in GLMN are a known cause of disease (Brouillard et al. 2013. PubMed ID: 23801931). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs762515373; hg19: chr1-92762964;