11-64809692-T-G

Position:

• chr11-64809692-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001370259.2(MEN1):​c.418A>C​(p.Ile140Leu) 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. I140F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_001370259.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MEN1. . Trascript score misZ 4.1921 (greater than threshold 3.09). GenCC has associacion of gene with multiple endocrine neoplasia type 1, pituitary gigantism, familial isolated hyperparathyroidism.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MEN1	NM_001370259.2	c.418A>C	p.Ile140Leu	missense_variant	2/10	ENST00000450708.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MEN1	ENST00000450708.7	c.418A>C	p.Ile140Leu	missense_variant	2/10	5	NM_001370259.2	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Benign	0.74
DEOGEN2	Uncertain	0.48	T;.;.;.;.;D;D;D;D;T;.;T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.94	D;D;.;.;D;.;.;D;.;D;D;D;.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	0.81	.;L;L;L;L;L;L;L;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.57	N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.72
Sift	Benign	0.93	T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;T;.;T;T;.;.
Polyphen		0.94, 0.019, 0.024	.;P;B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.63
MutPred		0.76		Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);Loss of methylation at K135 (P = 0.0947);
MVP		0.90
MPC		1.0
ClinPred		0.76	D
GERP RS		4.9
Varity_R		0.69
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs376510601; hg19: chr11-64577164;