1-92262939-AAT-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_053274.3(GLMN):c.1410-15_1410-14del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000901 in 959,728 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (2 hom.)
• Consequence: GLMN NM_053274.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.52

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 -16 ACMG points.

• BP6: Variant 1-92262939-AAT-A is Benign according to our data. Variant chr1-92262939-AAT-A is described in ClinVar as [Likely_benign]. Clinvar id is 298129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00203 (309/152332) while in subpopulation AFR AF= 0.00563 (234/41572). AF 95% confidence interval is 0.00504. There are 1 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 308 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLMN	NM_053274.3	c.1410-15_1410-14del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370360.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLMN	ENST00000370360.8	c.1410-15_1410-14del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_053274.3	P1
GLMN	ENST00000495106.5	c.*71-15_*71-14del		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1
GLMN	ENST00000463560.1	c.673-15_673-14del		splice_polypyrimidine_tract_variant, intron_variant		5
GLMN	ENST00000495852.6	c.633-15_633-14del		splice_polypyrimidine_tract_variant, intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00562

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000852

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000863 AC: 212 AN: 245622 Hom.: 0 AF XY: 0.000736 AC XY: 98 AN XY: 133160

Gnomad AFR exome AF: 0.00641

Gnomad AMR exome AF: 0.000409

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.000327

Gnomad NFE exome AF: 0.000804

Gnomad OTH exome AF: 0.000834

GnomAD4 exome AF: 0.000689 AC: 556 AN: 807396 Hom.: 2 AF XY: 0.000588 AC XY: 249 AN XY: 423740

Gnomad4 AFR exome AF: 0.00554

Gnomad4 AMR exome AF: 0.000354

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.0000136

Gnomad4 FIN exome AF: 0.000241

Gnomad4 NFE exome AF: 0.000721

Gnomad4 OTH exome AF: 0.000818

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74496

Gnomad4 AFR AF: 0.00563

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00223

Asia WGS AF: 0.000868 AC: 3 AN: 3472

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glomuvenous malformation Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.45		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs555041177; hg19: chr1-92728496;