dbSNP rs386134250: MEN1:p.Met1? (chr11-64810109-T-A) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_001370259.2(MEN1):c.1A>T(p.Met1?) variant causes a initiator codon 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 Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MEN1
NM_001370259.2 initiator_codon

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.25

Publications

16 publications found

Variant links:

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

MEN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 258 pathogenic variants. Next in-frame start position is after 228 codons. Genomic position: 64807653. Lost 0.372 part of the original CDS.

PS1

Another start lost variant in NM_001370259.2 (MEN1) was described as [Pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-64810109-T-A is Pathogenic according to our data. Variant chr11-64810109-T-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 428034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEN1	NM_001370259.2	MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 2 of 10	NP_001357188.2	O00255-2
MEN1	NM_001407150.1		c.1A>T	p.Met1?	initiator_codon	Exon 2 of 11	NP_001394079.1
MEN1	NM_001370251.2		c.1A>T	p.Met1?	initiator_codon	Exon 2 of 11	NP_001357180.2	A0A5F9ZHS3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEN1	ENST00000450708.7	TSL:5 MANE Select	c.1A>T	p.Met1?	initiator_codon	Exon 2 of 10	ENSP00000394933.3	O00255-2
MEN1	ENST00000312049.11	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 2 of 10	ENSP00000308975.6	O00255-2
MEN1	ENST00000424912.2	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 3 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1005854

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

484424

African (AFR)

AF:

0.00

AC:

AN:

23132

American (AMR)

AF:

0.00

AC:

AN:

28094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13112

East Asian (EAS)

AF:

0.00

AC:

AN:

13832

South Asian (SAS)

AF:

0.00

AC:

AN:

47692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

12600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3148

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

829652

Other (OTH)

AF:

0.00

AC:

AN:

34592

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Multiple endocrine neoplasia, type 1 (3)

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.88

MetaSVM

Pathogenic

1.1

PhyloP100

4.3

PROVEAN

Benign

-1.1

REVEL

Pathogenic

0.82

Sift

Uncertain

0.024

Sift4G

Pathogenic

0.0

Polyphen

0.65

Vest4

0.69

MutPred

0.73

Loss of helix (P = 0.028)

MVP

0.99

ClinPred

0.99

GERP RS

4.2

PromoterAI

-0.34

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.63

gMVP

0.52

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over