rs762515373

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1PP5_Very_StrongBS2

The NM_053274.3(GLMN):c.157_161del(p.Lys53Ter) 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 6.73

Variant links:

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]

GLMN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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].

BS2

High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLMN	NM_053274.3 linkuse as main transcript	c.157_161del	p.Lys53Ter	frameshift_variant	3/19	ENST00000370360.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLMN	ENST00000370360.8 linkuse as main transcript	c.157_161del	p.Lys53Ter	frameshift_variant	3/19	1	NM_053274.3	P1	Q92990-1
GLMN	ENST00000495106.5 linkuse as main transcript	c.157_161del	p.Lys53Ter	frameshift_variant, NMD_transcript_variant	3/18	1			Q92990-2

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151694

Hom.:

Cov.:

show subpopulations

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:

AN:

251380

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135848

show subpopulations

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.:

AF XY:

0.000109

AC XY:

AN XY:

725948

show subpopulations

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:

AN:

151694

Hom.:

Cov.:

AF XY:

0.0000405

AC XY:

AN XY:

74068

show subpopulations

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.:

Bravo

AF:

0.0000529

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glomuvenous malformation

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 02, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 06, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Dec 09, 2019	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. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2024

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; Suárez-Magdalena, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

GLMN-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 10, 2023

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 (https://gnomad.broadinstitute.org/variant/1-92762964-ATTCTT-A). 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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over