11-64810109-T-G

Variant names:

• chr11-64810109-T-G
• rs386134250
• NM_001370259.2:c.1A>C

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_001370259.2(MEN1):​c.1A>C​(p.Met1?) variant causes a initiator codon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.00024 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MEN1 NM_001370259.2 initiator_codon
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.25
• Publications: 16 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: Pathogenic. The variant received 20 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 258 pathogenic variants. Next in-frame start position is after 228 codons. Genomic position: 64807653. Lost 0.372 part of the original CDS.
• PS1: Another start lost variant in NM_001370259.2 (MEN1) was described as [Pathogenic] in ClinVar
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64810109-T-G is Pathogenic according to our data. Variant chr11-64810109-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 850884.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1A>C	p.Met1?	initiator_codon	Exon 2 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.1A>C	p.Met1?	initiator_codon	Exon 2 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1A>C	p.Met1?	initiator_codon	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.1A>C	p.Met1?	initiator_codon	Exon 2 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 2 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.1A>C	p.Met1?	initiator_codon	Exon 3 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD2 exomes AF: 0.0000374 AC: 6 AN: 160466 AF XY: 0.0000222

Gnomad AFR exome AF: 0.000233

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000828

Gnomad FIN exome AF: 0.000115

Gnomad NFE exome AF: 0.0000138

Gnomad OTH exome AF: 0.000252

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000242 AC: 243 AN: 1005232 Hom.: 0 Cov.: 36 AF XY: 0.000279 AC XY: 135 AN XY: 484064

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000389 AC: 9 AN: 23124

American (AMR) AF: 0.000285 AC: 8 AN: 28086

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 2 AN: 13100

East Asian (EAS) AF: 0.000362 AC: 5 AN: 13828

South Asian (SAS) AF: 0.000778 AC: 37 AN: 47558

European-Finnish (FIN) AF: 0.000636 AC: 8 AN: 12578

Middle Eastern (MID) AF: 0.000318 AC: 1 AN: 3146

European-Non Finnish (NFE) AF: 0.000183 AC: 152 AN: 829266

Other (OTH) AF: 0.000608 AC: 21 AN: 34546

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

Alfa AF: 0.000370 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Multiple endocrine neoplasia, type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		4.3
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.81
Sift	Uncertain	0.024	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.65	P
Vest4		0.69
MutPred		0.73		Loss of helix (P = 0.028)
MVP		0.99
ClinPred		0.52	D
GERP RS		4.2
PromoterAI		-0.35	Neutral
Varity_R		0.63
gMVP		0.52
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs386134250; hg19: chr11-64577581;