rs371192390

Variant names:

• chr11-64810080-C-A
• rs371192390
• NM_001370259.2:c.30G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-64810080-C-A
• chr11-64810080-C-G

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.30G>T​(p.Leu10Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000557 in 1,604,882 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L10L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 30)
  • Exomes 𝑓: 0.00051 (2 hom.)
• Consequence: MEN1 NM_001370259.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: 0.502
• Publications: 4 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=-0.34).
• BP6: Variant 11-64810080-C-A is Benign according to our data. Variant chr11-64810080-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 136169.
• BP7: Synonymous conserved (PhyloP=0.502 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00102 (155/151938) while in subpopulation NFE AF = 0.00132 (90/67974). AF 95% confidence interval is 0.0011. There are 1 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 155 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.30G>T	p.Leu10Leu	synonymous	Exon 2 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.30G>T	p.Leu10Leu	synonymous	Exon 2 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.30G>T	p.Leu10Leu	synonymous	Exon 2 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.30G>T	p.Leu10Leu	synonymous	Exon 2 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.30G>T	p.Leu10Leu	synonymous	Exon 2 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.30G>T	p.Leu10Leu	synonymous	Exon 3 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 151828 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00569

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000687 AC: 158 AN: 230010 AF XY: 0.000635

Gnomad AFR exome AF: 0.0000706

Gnomad AMR exome AF: 0.0000893

Gnomad ASJ exome AF: 0.00134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00467

Gnomad NFE exome AF: 0.000542

Gnomad OTH exome AF: 0.00105

GnomAD4 exome AF: 0.000509 AC: 739 AN: 1452944 Hom.: 2 Cov.: 37 AF XY: 0.000526 AC XY: 380 AN XY: 722296

African (AFR) AF: 0.0000300 AC: 1 AN: 33372

American (AMR) AF: 0.0000679 AC: 3 AN: 44156

Ashkenazi Jewish (ASJ) AF: 0.00131 AC: 34 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39456

South Asian (SAS) AF: 0.000211 AC: 18 AN: 85210

European-Finnish (FIN) AF: 0.00601 AC: 298 AN: 49620

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5702

European-Non Finnish (NFE) AF: 0.000316 AC: 351 AN: 1109400

Other (OTH) AF: 0.000533 AC: 32 AN: 60038

GnomAD4 genome AF: 0.00102 AC: 155 AN: 151938 Hom.: 1 Cov.: 30 AF XY: 0.00132 AC XY: 98 AN XY: 74254

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00569 AC: 60 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00132 AC: 90 AN: 67974

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.00135 Hom.: 1

Bravo AF: 0.000389

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	Multiple endocrine neoplasia, type 1 (6)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	1	-	Hyperparathyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	12
DANN	Benign	0.95
PhyloP100		0.50
PromoterAI		-0.078	Neutral
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs371192390; hg19: chr11-64577552;