chr1-92247877-C-T

Position:

• chr1-92247877-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PM2 PP3_Strong PP5_Moderate

The NM_053274.3(GLMN):​c.1585+1G>A variant causes a splice donor 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
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.71

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: Splicing 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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/exons	MANE	UniProt
GLMN	NM_053274.3	c.1585+1G>A		splice_donor_variant		ENST00000370360.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLMN	ENST00000370360.8	c.1585+1G>A		splice_donor_variant		1	NM_053274.3	P1
GLMN	ENST00000495106.5	c.*246+1G>A		splice_donor_variant, NMD_transcript_variant		1
GLMN	ENST00000495852.6	c.808+1G>A		splice_donor_variant		5
GLMN	ENST00000471465.1	n.531+1G>A		splice_donor_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 949450 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 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.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glomuvenous malformation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Aug 21, 2023

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	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Benign	0.59	D
MutationTaster	Benign	1.0	D;D
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.

Other links and lift over

hg19: chr1-92713434;