11-64808033-C-T

Variant names:

• chr11-64808033-C-T
• rs607969
• NM_001370259.2:c.512G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_001407150.1(MEN1):​c.527G>A​(p.Arg176Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,614,078 control chromosomes in the GnomAD database, including 313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (14 hom., cov: 32)
  • Exomes 𝑓: 0.018 (299 hom.)
• Consequence: MEN1 NM_001407150.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:27 O:2
• Conservation: PhyloP100: 2.73
• Publications: 49 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 -10 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 28 uncertain in NM_001407150.1
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. 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: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to multiple endocrine neoplasia type 1, hereditary pheochromocytoma-paraganglioma, pituitary gigantism, familial isolated hyperparathyroidism.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014003247).
• BP6: Variant 11-64808033-C-T is Benign according to our data. Variant chr11-64808033-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41854.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0127 (1935/152278) while in subpopulation NFE AF = 0.0213 (1447/68028). AF 95% confidence interval is 0.0204. There are 14 homozygotes in GnomAd4. There are 924 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1935 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407150.1. 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.512G>A	p.Arg171Gln	missense	Exon 3 of 10	NP_001357188.2
	MEN1	NM_001407150.1		c.527G>A	p.Arg176Gln	missense	Exon 3 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.512G>A	p.Arg171Gln	missense	Exon 3 of 11	NP_001357180.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEN1	ENST00000450708.7	TSL:5 MANE Select	c.512G>A	p.Arg171Gln	missense	Exon 3 of 10	ENSP00000394933.3
	MEN1	ENST00000312049.11	TSL:1	c.512G>A	p.Arg171Gln	missense	Exon 3 of 10	ENSP00000308975.6
	MEN1	ENST00000424912.2	TSL:1	c.512G>A	p.Arg171Gln	missense	Exon 4 of 11	ENSP00000388016.2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1935 AN: 152160 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00878

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00501

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.0120 AC: 3017 AN: 250912 AF XY: 0.0120

Gnomad AFR exome AF: 0.00456

Gnomad AMR exome AF: 0.00773

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.00724

Gnomad FIN exome AF: 0.00616

Gnomad NFE exome AF: 0.0199

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0181 AC: 26503 AN: 1461800 Hom.: 299 Cov.: 33 AF XY: 0.0174 AC XY: 12671 AN XY: 727198

African (AFR) AF: 0.00326 AC: 109 AN: 33480

American (AMR) AF: 0.00776 AC: 347 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00471 AC: 123 AN: 26136

East Asian (EAS) AF: 0.00421 AC: 167 AN: 39690

South Asian (SAS) AF: 0.00160 AC: 138 AN: 86252

European-Finnish (FIN) AF: 0.00605 AC: 323 AN: 53380

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5766

European-Non Finnish (NFE) AF: 0.0219 AC: 24399 AN: 1111986

Other (OTH) AF: 0.0142 AC: 856 AN: 60392

GnomAD4 genome AF: 0.0127 AC: 1935 AN: 152278 Hom.: 14 Cov.: 32 AF XY: 0.0124 AC XY: 924 AN XY: 74446

African (AFR) AF: 0.00436 AC: 181 AN: 41546

American (AMR) AF: 0.00877 AC: 134 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00502 AC: 26 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4824

European-Finnish (FIN) AF: 0.00612 AC: 65 AN: 10624

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0213 AC: 1447 AN: 68028

Other (OTH) AF: 0.0118 AC: 25 AN: 2116

Alfa AF: 0.0170 Hom.: 90

Bravo AF: 0.0121

TwinsUK AF: 0.0197 AC: 73

ALSPAC AF: 0.0174 AC: 67

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0209 AC: 180

ExAC AF: 0.0118 AC: 1427

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0182

EpiControl AF: 0.0198

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	8	Multiple endocrine neoplasia, type 1 (10)
-	-	7	not provided (7)
-	-	7	not specified (8)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	1	Hyperparathyroidism (1)
-	-	1	Multiple endocrine neoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	0.69	N
PhyloP100		2.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.43
Sift	Benign	0.10	T
Sift4G	Benign	0.15	T
Polyphen		0.76	P
Vest4		0.20
MPC		1.2
ClinPred		0.017	T
GERP RS		4.8
PromoterAI		0.039	Neutral
Varity_R		0.34
gMVP		0.78
Mutation Taster		=99/1	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: rs607969; hg19: chr11-64575505; COSMIC: COSV53640053; COSMIC: COSV53640053;