chr1-92247981-T-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBS1BS2_Supporting

The NM_053274.3(GLMN):​c.1482A>T​(p.Leu494Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,193,078 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 1 hom. )

Consequence

GLMN
NM_053274.3 missense

Scores

4
15

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0730
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.05642146).
BP6
Variant 1-92247981-T-A is Benign according to our data. Variant chr1-92247981-T-A is described in ClinVar as [Benign]. Clinvar id is 876494.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00016 (167/1040764) while in subpopulation SAS AF= 0.000979 (76/77638). AF 95% confidence interval is 0.000801. There are 1 homozygotes in gnomad4_exome. There are 105 alleles in male gnomad4_exome subpopulation. Median coverage is 15. This position pass quality control queck.
BS2
High AC in GnomAd4 at 11 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GLMNNM_053274.3 linkuse as main transcriptc.1482A>T p.Leu494Phe missense_variant 17/19 ENST00000370360.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GLMNENST00000370360.8 linkuse as main transcriptc.1482A>T p.Leu494Phe missense_variant 17/191 NM_053274.3 P1Q92990-1
GLMNENST00000495106.5 linkuse as main transcriptc.*143A>T 3_prime_UTR_variant, NMD_transcript_variant 16/181 Q92990-2
GLMNENST00000495852.6 linkuse as main transcriptc.705A>T p.Leu235Phe missense_variant 9/105
GLMNENST00000471465.1 linkuse as main transcriptn.428A>T non_coding_transcript_exon_variant 1/32

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152196
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000620
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000233
AC:
58
AN:
249216
Hom.:
0
AF XY:
0.000274
AC XY:
37
AN XY:
134846
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 SAS exome
AF:
0.00124
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000159
Gnomad OTH exome
AF:
0.000328
GnomAD4 exome
AF:
0.000160
AC:
167
AN:
1040764
Hom.:
1
Cov.:
15
AF XY:
0.000196
AC XY:
105
AN XY:
537058
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000979
Gnomad4 FIN exome
AF:
0.0000391
Gnomad4 NFE exome
AF:
0.000106
Gnomad4 OTH exome
AF:
0.000172
GnomAD4 genome
AF:
0.0000722
AC:
11
AN:
152314
Hom.:
0
Cov.:
32
AF XY:
0.0000806
AC XY:
6
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000621
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000158
Hom.:
0
Bravo
AF:
0.0000453
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000280
AC:
34
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glomuvenous malformation Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
-0.39
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0063
T;T
Eigen
Benign
-0.17
Eigen_PC
Benign
-0.098
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.76
T;T
M_CAP
Benign
0.0095
T
MetaRNN
Benign
0.056
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.0
M;.
MutationTaster
Benign
0.89
D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.99
N;.
REVEL
Benign
0.053
Sift
Benign
0.033
D;.
Sift4G
Uncertain
0.029
D;D
Polyphen
0.63
P;.
Vest4
0.34
MutPred
0.41
Loss of stability (P = 0.0918);.;
MVP
0.63
MPC
0.17
ClinPred
0.13
T
GERP RS
1.3
Varity_R
0.12
gMVP
0.51

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.

Other links and lift over

dbSNP: rs150536401; hg19: chr1-92713538; API