Genetic Variant MEN1:p.Pro69Thr (chr11-64809905-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_001370259.2(MEN1):c.205C>A(p.Pro69Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P69S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MEN1
NM_001370259.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.75

Publications

0 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: 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

MEN1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2 link	c.205C>A	p.Pro69Thr	missense_variant	Exon 2 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7 link	c.205C>A	p.Pro69Thr	missense_variant	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3		O00255-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1435998

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712452

African (AFR)

AF:

0.00

AC:

AN:

32834

American (AMR)

AF:

0.00

AC:

AN:

39464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25670

East Asian (EAS)

AF:

0.00

AC:

AN:

38102

South Asian (SAS)

AF:

0.00

AC:

AN:

83892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51740

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099126

Other (OTH)

AF:

0.00

AC:

AN:

59436

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Uncertain

0.56

D;.;.;.;.;D;D;D;D;D;.;D;.;.

Eigen

Benign

-0.057

Eigen_PC

Benign

0.028

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

T;T;.;.;T;.;.;T;.;T;T;T;.;T

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.55

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Benign

1.2

.;L;L;L;L;L;L;L;L;.;.;.;.;.

PhyloP100

4.8

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.33

N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Pathogenic

0.67

Sift

Benign

0.60

T;T;T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.70

T;T;T;T;T;T;T;T;T;.;T;T;.;.

Polyphen

0.42, 0.80, 0.47

.;B;P;P;P;P;P;P;P;.;.;.;.;.

Vest4

0.15

MutPred

0.37

Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);Gain of phosphorylation at P69 (P = 0.0349);

MVP

0.80

MPC

1.1

ClinPred

0.49

GERP RS

4.0

PromoterAI

0.035

Neutral

(source)

Varity_R

0.21

gMVP

0.56

Mutation Taster

=68/32

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over