1-92246595-G-C

Variant names:

• chr1-92246595-G-C
• rs751408583
• NM_053274.3:c.1720C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP3_Strong BS2_Supporting

The NM_053274.3(GLMN):​c.1720C>G​(p.Arg574Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000751 in 1,598,536 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: GLMN NM_053274.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.81
• Publications: 3 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: Uncertain_significance. The variant received 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.976
• BS2: High AC in GnomAdExome4 at 11 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1720C>G	p.Arg574Gly	missense	Exon 19 of 19	NP_444504.1	Q92990-1
	GLMN	NM_001319683.2		c.1678C>G	p.Arg560Gly	missense	Exon 18 of 18	NP_001306612.1	B4DJ85
	GLMN	NR_135089.2		n.1728C>G		non_coding_transcript_exon	Exon 18 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLMN	ENST00000370360.8	TSL:1 MANE Select	c.1720C>G	p.Arg574Gly	missense	Exon 19 of 19	ENSP00000359385.3	Q92990-1
	GLMN	ENST00000495106.5	TSL:1	n.*381C>G		non_coding_transcript_exon	Exon 18 of 18	ENSP00000436829.1	Q92990-2
	GLMN	ENST00000495106.5	TSL:1	n.*381C>G		3_prime_UTR	Exon 18 of 18	ENSP00000436829.1	Q92990-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 250742 AF XY: 0.00000738

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000760 AC: 11 AN: 1446492 Hom.: 0 Cov.: 27 AF XY: 0.00000277 AC XY: 2 AN XY: 720752

African (AFR) AF: 0.00 AC: 0 AN: 33202

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26014

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00 AC: 0 AN: 85946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1098044

Other (OTH) AF: 0.00 AC: 0 AN: 59942

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74226

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.91		Loss of stability (P = 0.0436)
MVP		0.86
MPC		0.70
ClinPred		0.95	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.85
Mutation Taster		=19/81	disease causing

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: rs751408583; hg19: chr1-92712152;