rs863224526

Variant names:

• chr11-64804738-C-A
• rs863224526
• NM_001370259.2:c.1429G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-64804738-C-A
• chr11-64804738-C-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000450708.7(MEN1):​c.1429G>T​(p.Glu477*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E477E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: MEN1 ENST00000450708.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 6.27
• Publications: 1 publications found

Genes affected

MEN1 (HGNC:7010): (menin 1) This gene encodes menin, a tumor suppressor associated with a syndrome known as multiple endocrine neoplasia type 1. Menin is a scaffold protein that functions in histone modification and epigenetic gene regulation. It is thought to regulate several pathways and processes by altering chromatin structure through the modification of histones. [provided by RefSeq, May 2019]

MEN1 Gene-Disease associations (from GenCC):

• multiple endocrine neoplasia type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Ambry Genetics
• familial isolated hyperparathyroidism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pituitary gigantism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 81 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64804738-C-A is Pathogenic according to our data. Variant chr11-64804738-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 216133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000450708.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	NM_001370259.2	MANE Select	c.1429G>T	p.Glu477*	stop_gained	Exon 10 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.1570G>T	p.Glu524*	stop_gained	Exon 11 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1555G>T	p.Glu519*	stop_gained	Exon 11 of 11	NP_001357180.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	ENST00000450708.7	TSL:5 MANE Select	c.1429G>T	p.Glu477*	stop_gained	Exon 10 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.1429G>T	p.Glu477*	stop_gained	Exon 10 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.1429G>T	p.Glu477*	stop_gained	Exon 11 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 42

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Multiple endocrine neoplasia, type 1 (4)
3	-	-	not provided (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.3
Vest4		0.78
GERP RS		4.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs863224526; hg19: chr11-64572210;