chr1-92246626-GAA-G

Variant names:

• chr1-92246626-GAA-G
• NM_053274.3:c.1687_1688delTT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_053274.3(GLMN):​c.1687_1688delTT​(p.Phe563HisfsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GLMN NM_053274.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

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 Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0549 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLMN	NM_053274.3	c.1687_1688delTT	p.Phe563HisfsTer3	frameshift_variant	Exon 19 of 19	ENST00000370360.8	NP_444504.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLMN	ENST00000370360.8	c.1687_1688delTT	p.Phe563HisfsTer3	frameshift_variant	Exon 19 of 19	1	NM_053274.3	ENSP00000359385.3
GLMN	ENST00000495106.5	n.*348_*349delTT		non_coding_transcript_exon_variant	Exon 18 of 18	1		ENSP00000436829.1
GLMN	ENST00000495106.5	n.*348_*349delTT		3_prime_UTR_variant	Exon 18 of 18	1		ENSP00000436829.1
GLMN	ENST00000471465.1	n.633_634delTT		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glomuvenous malformation Uncertain:1

Sep 01, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GLMN c.1687_1688del (p.Phe563HisfsTer3) variant was identified at an allelic fraction consistent with somatic origin. This variant, to our knowledge, has not been reported in the medical literature. This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant causes a frameshift by deleting two nucleotides, leading to a premature termination codon; however, because this occurs in the last exon, this is not predicted to lead to nonsense-mediated decay. Loss-of-function variants have been reported in glomuvenous malformation and Blue rubber bleb nevus syndrome (Brouillard P et al., PMID: 15689436, Borroni RG et al., PMID: 24961656; Borroni RG et al., PMID: 24345188; Brouillard P et al., PMID: 23801931; Amyere M et al., PMID: 23375657; Brouillard P et al., PMID: 11845407; Yin J et al., PMID: 31793416). A concurrent variant at a heterozygous allelic fraction, GLMN c.395-1G>C, is identified; however, whether these variants are in cis or trans, can not be determined by this assay. The GLMN c.1687_1688del (p.Phe563HisfsTer3) variant is predicted to result in a loss of function allele. The two-hit model for glomuvenous malformations involving the GLMN gene has been reported in the literature (Brouillard P et al., PMID: 23801931; Brouillard P et al., PMID: 15689436; Amyere M et al., PMID: 23375657; Amyere M et al., PMID: 23375657; Borroni RG et al., PMID: 24961656; Brouillard et al., PMID: 11845407). Due to limited information and based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the clinical significance of this variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-92712183;