rs201467961

Positions:

• chr1-92297394-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_053274.3(GLMN):​c.165+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,610,148 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0034 (26 hom.)
• Consequence: GLMN NM_053274.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.526

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-92297394-T-C is Benign according to our data. Variant chr1-92297394-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 298148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00255 (388/152062) while in subpopulation SAS AF= 0.00934 (45/4820). AF 95% confidence interval is 0.00717. There are 3 homozygotes in gnomad4. There are 202 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 388 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLMN	NM_053274.3	c.165+10A>G		intron_variant		ENST00000370360.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLMN	ENST00000370360.8	c.165+10A>G		intron_variant		1	NM_053274.3	P1
GLMN	ENST00000495106.5	c.165+10A>G		intron_variant, NMD_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00257 AC: 390 AN: 151946 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00933

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00296

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00297 AC: 747 AN: 251370 Hom.: 6 AF XY: 0.00359 AC XY: 488 AN XY: 135850

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00957

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00304

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00339 AC: 4942 AN: 1458086 Hom.: 26 Cov.: 29 AF XY: 0.00368 AC XY: 2671 AN XY: 725600

Gnomad4 AFR exome AF: 0.00186

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00925

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00334

Gnomad4 OTH exome AF: 0.00360

GnomAD4 genome AF: 0.00255 AC: 388 AN: 152062 Hom.: 3 Cov.: 30 AF XY: 0.00272 AC XY: 202 AN XY: 74344

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00458

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00934

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00297

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00249 Hom.: 0

Bravo AF: 0.00260

Asia WGS AF: 0.00433 AC: 16 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 03, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Glomuvenous malformation Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.4
DANN	Benign	0.84

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

LitVar

Other links and lift over

dbSNP: rs201467961; hg19: chr1-92762951;