rs541476418

Variant names:

• chr11-64810049-G-A
• rs541476418
• NM_001370259.2:c.61C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-64810049-G-A
• chr11-64810049-G-C
• chr11-64810049-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001370259.2(MEN1):​c.61C>T​(p.Arg21Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.05
• Publications: 3 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 32 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 113 curated pathogenic missense variants (we use a threshold of 10). The gene has 20 curated benign missense variants. Trascript score misZ: 4.1921 (above the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, pituitary gigantism, familial isolated hyperparathyroidism.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	NM_001370259.2	MANE Select	c.61C>T	p.Arg21Cys	missense	Exon 2 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.61C>T	p.Arg21Cys	missense	Exon 2 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.61C>T	p.Arg21Cys	missense	Exon 2 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.61C>T	p.Arg21Cys	missense	Exon 2 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.61C>T	p.Arg21Cys	missense	Exon 2 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.61C>T	p.Arg21Cys	missense	Exon 3 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1448706 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 720184

African (AFR) AF: 0.00 AC: 0 AN: 33166

American (AMR) AF: 0.00 AC: 0 AN: 44176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25792

East Asian (EAS) AF: 0.00 AC: 0 AN: 39222

South Asian (SAS) AF: 0.00 AC: 0 AN: 85432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50750

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104840

Other (OTH) AF: 0.00 AC: 0 AN: 59604

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Benign	0.69	N
PhyloP100		3.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.044	D
Polyphen		0.73	P
Vest4		0.51
MutPred		0.62		Gain of loop (P = 0.0195)
MVP		0.96
MPC		2.5
ClinPred		0.98	D
GERP RS		2.9
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.44
Mutation Taster		=49/51	disease causing

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: rs541476418; hg19: chr11-64577521;