11-64809692-T-G

Variant names:

• chr11-64809692-T-G
• rs376510601
• NM_001370259.2:c.418A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. 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.

• 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 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, pituitary gigantism, familial isolated hyperparathyroidism.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.418A>C	p.Ile140Leu	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	c.418A>C	p.Ile140Leu	missense_variant	Exon 2 of 10	5	NM_001370259.2	ENSP00000394933.3

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;.;.;.;.;.
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;