chr1-92246415-C-G

Variant names:

• chr1-92246415-C-G
• rs2046620
• NM_053274.3:c.*115G>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_053274.3(GLMN):​c.*115G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 638,150 control chromosomes in the GnomAD database, including 86,206 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (18164 hom., cov: 32)
  • Exomes 𝑓: 0.51 (68042 hom.)
• Consequence: GLMN NM_053274.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0740

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=-0.83).
• BP6: Variant 1-92246415-C-G is Benign according to our data. Variant chr1-92246415-C-G is described in ClinVar as [Benign]. Clinvar id is 298125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-92246415-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.942 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLMN	NM_053274.3	c.*115G>C		3_prime_UTR_variant	Exon 19 of 19	ENST00000370360.8	NP_444504.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLMN	ENST00000370360	c.*115G>C		3_prime_UTR_variant	Exon 19 of 19	1	NM_053274.3	ENSP00000359385.3
GLMN	ENST00000495106.5	n.*561G>C		downstream_gene_variant		1		ENSP00000436829.1
GLMN	ENST00000471465.1	n.*77G>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.475 AC: 72133 AN: 151772 Hom.: 18153 Cov.: 32

Gnomad AFR AF: 0.454

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.544

Gnomad EAS AF: 0.964

Gnomad SAS AF: 0.716

Gnomad FIN AF: 0.346

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.470

GnomAD4 exome AF: 0.507 AC: 246556 AN: 486260 Hom.: 68042 Cov.: 4 AF XY: 0.517 AC XY: 135696 AN XY: 262532

Gnomad4 AFR exome AF: 0.468

Gnomad4 AMR exome AF: 0.511

Gnomad4 ASJ exome AF: 0.530

Gnomad4 EAS exome AF: 0.961

Gnomad4 SAS exome AF: 0.708

Gnomad4 FIN exome AF: 0.365

Gnomad4 NFE exome AF: 0.446

Gnomad4 OTH exome AF: 0.509

GnomAD4 genome AF: 0.475 AC: 72164 AN: 151890 Hom.: 18164 Cov.: 32 AF XY: 0.478 AC XY: 35490 AN XY: 74234

Gnomad4 AFR AF: 0.454

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.544

Gnomad4 EAS AF: 0.964

Gnomad4 SAS AF: 0.715

Gnomad4 FIN AF: 0.346

Gnomad4 NFE AF: 0.444

Gnomad4 OTH AF: 0.477

Alfa AF: 0.449 Hom.: 1864

Bravo AF: 0.481

Asia WGS AF: 0.798 AC: 2754 AN: 3458

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Glomuvenous malformation Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.83
CADD	Benign	0.50
DANN	Benign	0.53

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: rs2046620; hg19: chr1-92711972; COSMIC: COSV64860075; COSMIC: COSV64860075;