NM_053274.3:c.1720C>T

Variant names:

• chr1-92246595-G-A
• rs751408583
• NM_053274.3:c.1720C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PVS1_Moderate PP5_Very_Strong BS2_Supporting

The NM_053274.3(GLMN):​c.1720C>T​(p.Arg574*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000899 in 1,446,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: GLMN NM_053274.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.81
• Publications: 3 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 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 0.0364 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PP5: Variant 1-92246595-G-A is Pathogenic according to our data. Variant chr1-92246595-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 618145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 13 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1720C>T	p.Arg574*	stop_gained	Exon 19 of 19	NP_444504.1	Q92990-1
	GLMN	NM_001319683.2		c.1678C>T	p.Arg560*	stop_gained	Exon 18 of 18	NP_001306612.1	B4DJ85
	GLMN	NR_135089.2		n.1728C>T		non_coding_transcript_exon	Exon 18 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLMN	ENST00000370360.8	TSL:1 MANE Select	c.1720C>T	p.Arg574*	stop_gained	Exon 19 of 19	ENSP00000359385.3	Q92990-1
	GLMN	ENST00000495106.5	TSL:1	n.*381C>T		non_coding_transcript_exon	Exon 18 of 18	ENSP00000436829.1	Q92990-2
	GLMN	ENST00000495106.5	TSL:1	n.*381C>T		3_prime_UTR	Exon 18 of 18	ENSP00000436829.1	Q92990-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250742 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000899 AC: 13 AN: 1446488 Hom.: 0 Cov.: 27 AF XY: 0.0000111 AC XY: 8 AN XY: 720750

African (AFR) AF: 0.00 AC: 0 AN: 33202

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 85946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.0000109 AC: 12 AN: 1098040

Other (OTH) AF: 0.0000167 AC: 1 AN: 59942

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Vascular skin disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		3.8
Vest4		0.78
GERP RS		5.1
Mutation Taster		=4/196	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs751408583; hg19: chr1-92712152; COSMIC: COSV64860439; COSMIC: COSV64860439;