chr1-92263655-AC-A

Variant names:

• chr1-92263655-AC-A
• rs2100872124
• NM_053274.3:c.1376delG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_053274.3(GLMN):​c.1376delG​(p.Gly459ValfsTer17) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GLMN NM_053274.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 5.62
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• glomuvenous malformation

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-92263655-AC-A is Pathogenic according to our data. Variant chr1-92263655-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1323020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053274.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLMN	NM_053274.3	MANE Select	c.1376delG	p.Gly459ValfsTer17	frameshift	Exon 15 of 19	NP_444504.1	Q92990-1
	GLMN	NM_001319683.2		c.1334delG	p.Gly445ValfsTer17	frameshift	Exon 14 of 18	NP_001306612.1	B4DJ85
	GLMN	NR_135089.2		n.1384delG		non_coding_transcript_exon	Exon 14 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLMN	ENST00000370360.8	TSL:1 MANE Select	c.1376delG	p.Gly459ValfsTer17	frameshift	Exon 15 of 19	ENSP00000359385.3	Q92990-1
	GLMN	ENST00000495106.5	TSL:1	n.*37delG		non_coding_transcript_exon	Exon 14 of 18	ENSP00000436829.1	Q92990-2
	GLMN	ENST00000495106.5	TSL:1	n.*37delG		3_prime_UTR	Exon 14 of 18	ENSP00000436829.1	Q92990-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Glomuvenous malformation (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2100872124; hg19: chr1-92729212;