rs770780171

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_053274.3(GLMN):c.108C>A(p.Cys36*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,252 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GLMN
NM_053274.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.796

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

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

GLMN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 1-92297461-G-T is Pathogenic according to our data. Variant chr1-92297461-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 523551.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLMN	NM_053274.3 link	c.108C>A	p.Cys36*	stop_gained	Exon 3 of 19	ENST00000370360.8	NP_444504.1	Q92990-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLMN	ENST00000370360.8 link	c.108C>A	p.Cys36*	stop_gained	Exon 3 of 19	1	NM_053274.3	ENSP00000359385.3	Q92990-1
GLMN	ENST00000495106.5 link	n.108C>A		non_coding_transcript_exon_variant	Exon 3 of 18	1		ENSP00000436829.1	Q92990-2
GLMN	ENST00000487911.1 link	n.*60C>A		downstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251384

AF XY:

0.00000736

show subpopulations

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460252

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726566

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110670

Other (OTH)

AF:

0.0000166

AC:

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000218

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GLMN: PVS1, PM2, PP4, PS4:Supporting -

Clinical Genetics, Academic Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 19, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32538359, 23375657, 15689436, 24345188, 25525159, 19250411, 28655553, 34426522, 35216474, 35807022, 35732373, 11845407) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Glomuvenous malformation

Pathogenic:3

Dec 08, 2022

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2, PP5 -

Aug 12, 2023

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 supporting -

Jan 16, 2020

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Venous malformation

Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.13

Eigen_PC

Benign

-0.098

FATHMM_MKL

Uncertain

0.89

PhyloP100

0.80

Vest4

0.82

GERP RS

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over