11-64806117-T-C

Variant names:

• chr11-64806117-T-C
• rs669976
• NM_001370259.2:c.1049+115A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001370259.2(MEN1):​c.1049+115A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,405,598 control chromosomes in the GnomAD database, including 12,604 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1537 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11067 hom.)
• Consequence: MEN1 NM_001370259.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.270
• Publications: 24 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 11-64806117-T-C is Benign according to our data. Variant chr11-64806117-T-C is described in ClinVar as Benign. ClinVar VariationId is 1233206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MEN1	NM_001370259.2	c.1049+115A>G		intron_variant	Intron 7 of 9	ENST00000450708.7	NP_001357188.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MEN1	ENST00000450708.7	c.1049+115A>G		intron_variant	Intron 7 of 9	5	NM_001370259.2	ENSP00000394933.3

Frequencies

GnomAD3 genomes AF: 0.128 AC: 19445 AN: 151838 Hom.: 1533 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.242

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.135

GnomAD4 exome AF: 0.118 AC: 148053 AN: 1253644 Hom.: 11067 Cov.: 17 AF XY: 0.120 AC XY: 75390 AN XY: 629056

African (AFR) AF: 0.106 AC: 3151 AN: 29596

American (AMR) AF: 0.304 AC: 12600 AN: 41476

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3436 AN: 23778

East Asian (EAS) AF: 0.316 AC: 12007 AN: 38054

South Asian (SAS) AF: 0.190 AC: 15075 AN: 79434

European-Finnish (FIN) AF: 0.122 AC: 4848 AN: 39816

Middle Eastern (MID) AF: 0.106 AC: 474 AN: 4458

European-Non Finnish (NFE) AF: 0.0953 AC: 89892 AN: 943448

Other (OTH) AF: 0.123 AC: 6570 AN: 53584

GnomAD4 genome AF: 0.128 AC: 19476 AN: 151954 Hom.: 1537 Cov.: 32 AF XY: 0.135 AC XY: 9998 AN XY: 74268

African (AFR) AF: 0.101 AC: 4186 AN: 41464

American (AMR) AF: 0.242 AC: 3693 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 517 AN: 3468

East Asian (EAS) AF: 0.281 AC: 1449 AN: 5160

South Asian (SAS) AF: 0.198 AC: 953 AN: 4806

European-Finnish (FIN) AF: 0.131 AC: 1380 AN: 10560

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6948 AN: 67912

Other (OTH) AF: 0.139 AC: 293 AN: 2110

Alfa AF: 0.0993 Hom.: 1377

Bravo AF: 0.135

Asia WGS AF: 0.253 AC: 879 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.88
PhyloP100		0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs669976; hg19: chr11-64573589; COSMIC: COSV53644150; COSMIC: COSV53644150;