1-92248000-TGAAA-T

Variant names:

• chr1-92248000-TGAAA-T
• rs535813981
• NM_053274.3:c.1474-15_1474-12delTTTC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_053274.3(GLMN):​c.1474-15_1474-12delTTTC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,015,914 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (14 hom.)
• Consequence: GLMN NM_053274.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.95
• Publications: 0 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-92248000-TGAAA-T is Benign according to our data. Variant chr1-92248000-TGAAA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 298128.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00196 (298/152286) while in subpopulation AMR AF = 0.00693 (106/15296). AF 95% confidence interval is 0.00586. There are 2 homozygotes in GnomAd4. There are 169 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 298 AD gene.

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.1474-15_1474-12delTTTC		intron	N/A	NP_444504.1	Q92990-1
	GLMN	NM_001319683.2		c.1432-15_1432-12delTTTC		intron	N/A	NP_001306612.1	B4DJ85
	GLMN	NR_135089.2		n.1482-15_1482-12delTTTC		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLMN	ENST00000370360.8	TSL:1 MANE Select	c.1474-15_1474-12delTTTC		intron	N/A	ENSP00000359385.3	Q92990-1
	GLMN	ENST00000495106.5	TSL:1	n.*135-15_*135-12delTTTC		intron	N/A	ENSP00000436829.1	Q92990-2
	GLMN	ENST00000931421.1		c.1540-15_1540-12delTTTC		intron	N/A	ENSP00000601480.1

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152168 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00224 AC: 556 AN: 247756 AF XY: 0.00247

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.00320

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000155

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00395

GnomAD4 exome AF: 0.00199 AC: 1720 AN: 863628 Hom.: 14 AF XY: 0.00216 AC XY: 983 AN XY: 454928

African (AFR) AF: 0.000360 AC: 8 AN: 22218

American (AMR) AF: 0.00308 AC: 135 AN: 43870

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 391 AN: 22334

East Asian (EAS) AF: 0.00 AC: 0 AN: 36922

South Asian (SAS) AF: 0.00290 AC: 215 AN: 74160

European-Finnish (FIN) AF: 0.000180 AC: 9 AN: 49978

Middle Eastern (MID) AF: 0.0242 AC: 112 AN: 4620

European-Non Finnish (NFE) AF: 0.00122 AC: 696 AN: 568814

Other (OTH) AF: 0.00378 AC: 154 AN: 40712

GnomAD4 genome AF: 0.00196 AC: 298 AN: 152286 Hom.: 2 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74472

African (AFR) AF: 0.000313 AC: 13 AN: 41554

American (AMR) AF: 0.00693 AC: 106 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00141 AC: 96 AN: 68012

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00400 Hom.: 1

Bravo AF: 0.00227

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Glomuvenous malformation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs535813981; hg19: chr1-92713557;