11-64807653-T-G

Variant names:

• chr11-64807653-T-G
• NM_001370259.2:c.682A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001370259.2(MEN1):​c.682A>C​(p.Met228Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3402177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.682A>C	p.Met228Leu	missense_variant	Exon 4 of 10	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.682A>C	p.Met228Leu	missense_variant	Exon 4 of 10	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Uncertain	0.50	D;.;.;.;.;D;D;D;D;T;.;D
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T;T;.;.;T;.;.;T;.;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.2	.;.;.;.;.;L;L;L;L;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.31	N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.16	T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T;T;T;.;T;T
Polyphen		0.0, 0.011, 0.031	.;B;B;B;B;B;B;B;B;.;.;.
Vest4		0.35
MutPred		0.72		.;.;.;.;.;Loss of catalytic residue at M233 (P = 0.02);Loss of catalytic residue at M233 (P = 0.02);Loss of catalytic residue at M233 (P = 0.02);Loss of catalytic residue at M233 (P = 0.02);.;.;.;
MVP		0.79
MPC		0.97
ClinPred		0.40	T
GERP RS		2.4
Varity_R		0.33
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-64575125;