chr11-64810111-G-A

Variant names:

• chr11-64810111-G-A
• rs653534
• NM_001370259.2:c.-2C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001370259.2(MEN1):​c.-2C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000423 in 1,417,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: MEN1 NM_001370259.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.74
• Publications: 0 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370259.2. 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
	MEN1	NM_001370259.2	MANE Select	c.-2C>T		5_prime_UTR	Exon 2 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.-2C>T		5_prime_UTR	Exon 2 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.-2C>T		5_prime_UTR	Exon 2 of 11	NP_001357180.2	A0A5F9ZHS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	ENST00000450708.7	TSL:5 MANE Select	c.-2C>T		5_prime_UTR	Exon 2 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.-2C>T		5_prime_UTR	Exon 2 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.-2C>T		5_prime_UTR	Exon 3 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000423 AC: 6 AN: 1417918 Hom.: 0 Cov.: 37 AF XY: 0.00000855 AC XY: 6 AN XY: 701622

African (AFR) AF: 0.00 AC: 0 AN: 32696

American (AMR) AF: 0.00 AC: 0 AN: 41188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25478

East Asian (EAS) AF: 0.00 AC: 0 AN: 38216

South Asian (SAS) AF: 0.00 AC: 0 AN: 82602

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5064

European-Non Finnish (NFE) AF: 0.00000549 AC: 6 AN: 1093664

Other (OTH) AF: 0.00 AC: 0 AN: 58720

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Multiple endocrine neoplasia, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	0.99
PhyloP100		2.7
PromoterAI		-0.23	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=295/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs653534; hg19: chr11-64577583;