rs778651218

Variant names:

• chr1-92262862-CTTGA-C
• rs778651218
• NM_053274.3:c.1470_1473delTCAA

Your query was ambiguous. Multiple possible variants found:

• chr1-92262862-CTTGA-C
• chr1-92262862-CTTGA-CTTGATTGA

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_053274.3(GLMN):​c.1470_1473delTCAA​(p.Asn490fs) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000011 in 1,095,172 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: GLMN NM_053274.3 frameshift, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 4.78
• 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: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-92262862-CTTGA-C is Pathogenic according to our data. Variant chr1-92262862-CTTGA-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 987245.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1470_1473delTCAA	p.Asn490fs	frameshift splice_region	Exon 16 of 19	NP_444504.1	Q92990-1
	GLMN	NM_001319683.2		c.1428_1431delTCAA	p.Asn476fs	frameshift splice_region	Exon 15 of 18	NP_001306612.1	B4DJ85
	GLMN	NR_135089.2		n.1478_1481delTCAA		splice_region non_coding_transcript_exon	Exon 15 of 18

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLMN	ENST00000370360.8	TSL:1 MANE Select	c.1470_1473delTCAA	p.Asn490fs	frameshift splice_region	Exon 16 of 19	ENSP00000359385.3	Q92990-1
	GLMN	ENST00000495106.5	TSL:1	n.*131_*134delTCAA		splice_region non_coding_transcript_exon	Exon 15 of 18	ENSP00000436829.1	Q92990-2
	GLMN	ENST00000495106.5	TSL:1	n.*131_*134delTCAA		3_prime_UTR	Exon 15 of 18	ENSP00000436829.1	Q92990-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 247624 AF XY: 0.0000224

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: 0.0000358

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000117 AC: 11 AN: 942972 Hom.: 0 AF XY: 0.0000103 AC XY: 5 AN XY: 487482

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

African (AFR) AF: 0.00 AC: 0 AN: 24246

American (AMR) AF: 0.00 AC: 0 AN: 42696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22136

East Asian (EAS) AF: 0.00 AC: 0 AN: 36464

South Asian (SAS) AF: 0.00 AC: 0 AN: 75868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50478

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4684

European-Non Finnish (NFE) AF: 0.0000171 AC: 11 AN: 644016

Other (OTH) AF: 0.00 AC: 0 AN: 42384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000910319), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74360

African (AFR) AF: 0.0000241 AC: 1 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 1

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

Other links and lift over

dbSNP: rs778651218; hg19: chr1-92728419;