11-64807684-AG-AGG

Variant names:

• chr11-64807684-A-AG
• rs772016629
• NM_001370259.2:c.655-5dupC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001370259.2(MEN1):​c.655-5dupC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: MEN1 NM_001370259.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.397
• Publications: 1 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 -9 ACMG points.

• BP6: Variant 11-64807684-A-AG is Benign according to our data. Variant chr11-64807684-A-AG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 371885.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000677 (99/1461532) while in subpopulation EAS AF = 0.00111 (44/39698). AF 95% confidence interval is 0.000848. There are 0 homozygotes in GnomAdExome4. There are 46 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 13 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.655-5dupC		splice_region intron	N/A	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.670-5dupC		splice_region intron	N/A	NP_001394079.1
	MEN1	NM_001370251.2		c.655-5dupC		splice_region intron	N/A	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.655-5dupC		splice_region intron	N/A	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.655-5dupC		splice_region intron	N/A	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.655-5dupC		splice_region intron	N/A	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152076 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000479 AC: 12 AN: 250776 AF XY: 0.0000369

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461532 Hom.: 0 Cov.: 33 AF XY: 0.0000633 AC XY: 46 AN XY: 727020

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00111 AC: 44 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86114

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000414 AC: 46 AN: 1111948

Other (OTH) AF: 0.0000497 AC: 3 AN: 60388

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74402

African (AFR) AF: 0.000168 AC: 7 AN: 41548

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs772016629; hg19: chr11-64575156; COSMIC: COSV99581608; COSMIC: COSV99581608;