rs138770431

Variant names:

• chr11-64805088-C-T
• rs138770431
• NM_001370259.2:c.1296G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001370259.2(MEN1):​c.1296G>A​(p.Leu432Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,614,160 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: MEN1 NM_001370259.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:18
• Conservation: PhyloP100: -0.0480
• Publications: 5 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 11-64805088-C-T is Benign according to our data. Variant chr11-64805088-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 36524.
• BP7: Synonymous conserved (PhyloP=-0.048 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00121 (185/152362) while in subpopulation NFE AF = 0.00178 (121/68032). AF 95% confidence interval is 0.00152. There are 2 homozygotes in GnomAd4. There are 83 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 185 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	NM_001370259.2	MANE Select	c.1296G>A	p.Leu432Leu	synonymous	Exon 9 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.1437G>A	p.Leu479Leu	synonymous	Exon 10 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1422G>A	p.Leu474Leu	synonymous	Exon 10 of 11	NP_001357180.2	A0A5F9ZHS3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	ENST00000450708.7	TSL:5 MANE Select	c.1296G>A	p.Leu432Leu	synonymous	Exon 9 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.1296G>A	p.Leu432Leu	synonymous	Exon 9 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.1296G>A	p.Leu432Leu	synonymous	Exon 10 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 185 AN: 152244 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00115 AC: 289 AN: 251196 AF XY: 0.00121

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00166

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00147 AC: 2156 AN: 1461798 Hom.: 3 Cov.: 56 AF XY: 0.00144 AC XY: 1048 AN XY: 727206

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.00107 AC: 48 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000626 AC: 54 AN: 86258

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53370

Middle Eastern (MID) AF: 0.00469 AC: 27 AN: 5760

European-Non Finnish (NFE) AF: 0.00168 AC: 1866 AN: 1111992

Other (OTH) AF: 0.00147 AC: 89 AN: 60390

GnomAD4 genome AF: 0.00121 AC: 185 AN: 152362 Hom.: 2 Cov.: 34 AF XY: 0.00111 AC XY: 83 AN XY: 74508

African (AFR) AF: 0.000673 AC: 28 AN: 41584

American (AMR) AF: 0.000784 AC: 12 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00178 AC: 121 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.00144

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (5)
-	-	4	Multiple endocrine neoplasia, type 1 (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	-	Hyperparathyroidism (1)
-	-	1	MEN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	6.2
DANN	Benign	0.86
PhyloP100		-0.048
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs138770431; hg19: chr11-64572560;