rs145762716

Positions:

chr1-92271627-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_053274.3(GLMN):c.761C>G(p.Pro254Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000288 in 1,612,426 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

GLMN
NM_053274.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.28

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 links:

GLMN (HGNC:):

GLMN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00536716).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000375 (57/152092) while in subpopulation EAS AF= 0.011 (57/5166). AF 95% confidence interval is 0.00874. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLMN	NM_053274.3 linkuse as main transcript	c.761C>G	p.Pro254Arg	missense_variant	8/19	ENST00000370360.8	NP_444504.1	Q92990-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GLMN	ENST00000370360.8 linkuse as main transcript	c.761C>G	p.Pro254Arg	missense_variant	8/19	1	NM_053274.3	ENSP00000359385.3	Q92990-1
GLMN	ENST00000495106.5 linkuse as main transcript	n.761C>G		non_coding_transcript_exon_variant	8/18	1		ENSP00000436829.1	Q92990-2
GLMN	ENST00000495852.6 linkuse as main transcript	c.26C>G	p.Pro9Arg	missense_variant	1/10	5		ENSP00000469157.2	M0QXG8
GLMN	ENST00000463560.1 linkuse as main transcript	c.128C>G	p.Pro43Arg	missense_variant	2/9	5		ENSP00000468973.1	M0QX84

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0110

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000967

AC:

243

AN:

251224

Hom.:

AF XY:

0.000751

AC XY:

102

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0132

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000279

AC:

408

AN:

1460334

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

196

AN XY:

726616

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00945

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000375

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0110

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000263

Hom.:

Bravo

AF:

0.000476

ExAC

AF:

0.000848

AC:

103

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Blue rubber bleb nevus

Uncertain:1

Uncertain significance, criteria provided, single submitter

in vitro;research

Laboratory of Molecular Genetics, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences

- -

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

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.020

T;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.79

T;T

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.23

Sift

Benign

0.099

T;.

Sift4G

Benign

0.13

T;T

Polyphen

0.93

P;.

Vest4

0.40

MVP

0.80

MPC

0.36

ClinPred

0.11

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.10

gMVP

0.24

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over