1-92248000-TGAAA-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_053274.3(GLMN):c.1474-15_1474-12del 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 0.00199 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.95

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 -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 id is 298128.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-92248000-TGAAA-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 299 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLMN	NM_053274.3	c.1474-15_1474-12del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000370360.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLMN	ENST00000370360.8	c.1474-15_1474-12del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_053274.3	P1
GLMN	ENST00000495106.5	c.*135-15_*135-12del		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1
GLMN	ENST00000495852.6	c.697-15_697-12del		splice_polypyrimidine_tract_variant, intron_variant		5
GLMN	ENST00000471465.1	n.405_408del		non_coding_transcript_exon_variant	1/3	2

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

GnomAD3 exomes AF: 0.00224 AC: 556 AN: 247756 Hom.: 3 AF XY: 0.00247 AC XY: 331 AN XY: 134120

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 SAS exome AF: 0.00247

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

Gnomad4 AFR exome AF: 0.000360

Gnomad4 AMR exome AF: 0.00308

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00290

Gnomad4 FIN exome AF: 0.000180

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.00378

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

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00400 Hom.: 1

Bravo AF: 0.00227

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glomuvenous malformation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs535813981; hg19: chr1-92713557;