Genetic Variant GLMN:c.1585+1G>A (chr1-92247877-C-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_053274.3(GLMN):c.1585+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GLMN
NM_053274.3 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.71

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.8, offset of 4, new splice context is: ttgGTaatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-92247877-C-T is Pathogenic according to our data. Variant chr1-92247877-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2672221.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLMN	NM_053274.3 link	c.1585+1G>A		splice_donor_variant, intron_variant	Intron 17 of 18	ENST00000370360.8	NP_444504.1	Q92990-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLMN	ENST00000370360.8 link	c.1585+1G>A	splice_donor_variant, intron_variant	Intron 17 of 18	1	NM_053274.3	ENSP00000359385.3	Q92990-1
GLMN	ENST00000495106.5 link	n.*246+1G>A	splice_donor_variant, intron_variant	Intron 16 of 17	1		ENSP00000436829.1	Q92990-2
GLMN	ENST00000495852.6 link	c.808+1G>A	splice_donor_variant, intron_variant	Intron 9 of 9	5		ENSP00000469157.2	M0QXG8
GLMN	ENST00000471465.1 link	n.531+1G>A	splice_donor_variant, intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

949450

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

495418

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Glomuvenous malformation

Pathogenic:1

Aug 21, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GLMN c.1585+1G>A variant was identified at a near heterozygous allelic fraction. This variant, to our knowledge, has not been reported in the medical literature. Loss-of-function variants, including those impacting splice sites, 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). The GLMN c.1585+1G>A variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs within the canonical splice donor site, which is predicted to cause the skipping of the exon, leading to an out-of-frame transcript. Another variant at this position, c.1585+1G>T, has been reported in one individual with vascular malformations (Li D et al., PMID: 37264205, ClinVar Variation ID: 90837). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the GLMN c.1585+1G>A variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Benign

0.59

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.81

Position offset: -3

DS_DL_spliceai

1.0

Position offset: 1

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over