11-64804546-T-C

Variant names:

• chr11-64804546-T-C
• rs2959656
• NM_001370259.2:c.1621A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001370259.2(MEN1):​c.1621A>G​(p.Thr541Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.97 in 1,613,650 control chromosomes in the GnomAD database, including 763,565 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T541E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.90 (62591 hom., cov: 33)
  • Exomes 𝑓: 0.98 (700974 hom.)
• Consequence: MEN1 NM_001370259.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.139
• Publications: 80 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 -17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 31 uncertain in NM_001370259.2
• PP2: Missense variant in the MEN1 gene, where missense mutations are typically associated with disease (based on misZ statistic). 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: 4.1921 (above 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=6.717767E-7).
• BP6: Variant 11-64804546-T-C is Benign according to our data. Variant chr11-64804546-T-C is described in ClinVar as Benign. ClinVar VariationId is 134640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.99 is higher than 0.05.

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.1621A>G	p.Thr541Ala	missense	Exon 10 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.1762A>G	p.Thr588Ala	missense	Exon 11 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1747A>G	p.Thr583Ala	missense	Exon 11 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.1621A>G	p.Thr541Ala	missense	Exon 10 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.1621A>G	p.Thr541Ala	missense	Exon 10 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.1621A>G	p.Thr541Ala	missense	Exon 11 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes AF: 0.898 AC: 136517 AN: 152104 Hom.: 62559 Cov.: 33

Gnomad AFR AF: 0.713

Gnomad AMI AF: 0.993

Gnomad AMR AF: 0.903

Gnomad ASJ AF: 0.997

Gnomad EAS AF: 0.701

Gnomad SAS AF: 0.986

Gnomad FIN AF: 0.983

Gnomad MID AF: 0.972

Gnomad NFE AF: 0.996

Gnomad OTH AF: 0.924

GnomAD2 exomes AF: 0.937 AC: 235276 AN: 250986 AF XY: 0.949

Gnomad AFR exome AF: 0.706

Gnomad AMR exome AF: 0.881

Gnomad ASJ exome AF: 0.996

Gnomad EAS exome AF: 0.697

Gnomad FIN exome AF: 0.982

Gnomad NFE exome AF: 0.996

Gnomad OTH exome AF: 0.964

GnomAD4 exome AF: 0.977 AC: 1428180 AN: 1461428 Hom.: 700974 Cov.: 69 AF XY: 0.979 AC XY: 712107 AN XY: 727040

African (AFR) AF: 0.700 AC: 23446 AN: 33480

American (AMR) AF: 0.884 AC: 39541 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 26016 AN: 26134

East Asian (EAS) AF: 0.733 AC: 29102 AN: 39700

South Asian (SAS) AF: 0.994 AC: 85700 AN: 86258

European-Finnish (FIN) AF: 0.982 AC: 52055 AN: 52984

Middle Eastern (MID) AF: 0.983 AC: 5670 AN: 5768

European-Non Finnish (NFE) AF: 0.997 AC: 1108718 AN: 1111998

Other (OTH) AF: 0.959 AC: 57932 AN: 60386

GnomAD4 genome AF: 0.897 AC: 136597 AN: 152222 Hom.: 62591 Cov.: 33 AF XY: 0.897 AC XY: 66721 AN XY: 74400

African (AFR) AF: 0.713 AC: 29603 AN: 41494

American (AMR) AF: 0.903 AC: 13811 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 3461 AN: 3472

East Asian (EAS) AF: 0.701 AC: 3616 AN: 5158

South Asian (SAS) AF: 0.986 AC: 4759 AN: 4828

European-Finnish (FIN) AF: 0.983 AC: 10446 AN: 10622

Middle Eastern (MID) AF: 0.969 AC: 285 AN: 294

European-Non Finnish (NFE) AF: 0.996 AC: 67756 AN: 68030

Other (OTH) AF: 0.925 AC: 1954 AN: 2112

Alfa AF: 0.957 Hom.: 101603

Bravo AF: 0.881

TwinsUK AF: 0.997 AC: 3696

ALSPAC AF: 0.996 AC: 3839

ESP6500AA AF: 0.738 AC: 3247

ESP6500EA AF: 0.996 AC: 8559

ExAC AF: 0.938 AC: 113841

Asia WGS AF: 0.868 AC: 3022 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	1.6
DANN	Benign	0.54
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0060	N
LIST_S2	Benign	0.029	T
MetaRNN	Benign	6.7e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.14
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.30
Sift	Benign	0.87	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.053
MPC		1.0
ClinPred		0.0012	T
GERP RS		3.4
Varity_R		0.021
gMVP		0.27
Mutation Taster		=100/0	polymorphism (auto)

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: rs2959656; hg19: chr11-64572018; COSMIC: COSV53639974; COSMIC: COSV53639974;