chr1-92247890-T-A

Variant names:

• chr1-92247890-T-A
• rs1406647358
• NM_053274.3:c.1573A>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_053274.3(GLMN):​c.1573A>T​(p.Lys525*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000181 in 1,107,856 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: GLMN NM_053274.3 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.43
• 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 1-92247890-T-A is Pathogenic according to our data. Variant chr1-92247890-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3382812.Status of the report is criteria_provided_single_submitter, 1 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.1573A>T	p.Lys525*	stop_gained	Exon 17 of 19	NP_444504.1	Q92990-1
	GLMN	NM_001319683.2		c.1531A>T	p.Lys511*	stop_gained	Exon 16 of 18	NP_001306612.1	B4DJ85
	GLMN	NR_135089.2		n.1581A>T		non_coding_transcript_exon	Exon 16 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLMN	ENST00000370360.8	TSL:1 MANE Select	c.1573A>T	p.Lys525*	stop_gained	Exon 17 of 19	ENSP00000359385.3	Q92990-1
	GLMN	ENST00000495106.5	TSL:1	n.*234A>T		non_coding_transcript_exon	Exon 16 of 18	ENSP00000436829.1	Q92990-2
	GLMN	ENST00000495106.5	TSL:1	n.*234A>T		3_prime_UTR	Exon 16 of 18	ENSP00000436829.1	Q92990-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000181 AC: 2 AN: 1107856 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 568358

African (AFR) AF: 0.00 AC: 0 AN: 26742

American (AMR) AF: 0.00 AC: 0 AN: 44224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23864

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 37960

South Asian (SAS) AF: 0.00 AC: 0 AN: 79076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5052

European-Non Finnish (NFE) AF: 0.00000126 AC: 1 AN: 790816

Other (OTH) AF: 0.00 AC: 0 AN: 48486

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Glomuvenous malformation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		5.4
Vest4		0.85
GERP RS		6.0
Mutation Taster		=0/200	disease causing (fs/PTC)

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: rs1406647358; hg19: chr1-92713447;