rs587777949

Variant names:

• chr11-64810267-C-T
• rs587777949
• NM_001370259.2:c.-23-135G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-64810267-C-T
• chr11-64810267-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_001407150.1(MEN1):​c.-24+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000043 in 627,826 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (1 hom.)
• Consequence: MEN1 NM_001407150.1 splice_donor, intron
• Scores: Splicing: ADA: 0.0001366
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: -0.758
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• BS2: High AC in GnomAd4 at 17 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.-23-135G>A		intron	N/A	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.-24+1G>A		splice_donor intron	N/A	NP_001394079.1
	MEN1	NM_001370251.2		c.-23-135G>A		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.-23-135G>A		intron	N/A	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.-23-135G>A		intron	N/A	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.-23-135G>A		intron	N/A	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000210 AC: 10 AN: 475674 Hom.: 1 Cov.: 6 AF XY: 0.0000160 AC XY: 4 AN XY: 249794

African (AFR) AF: 0.00 AC: 0 AN: 12876

American (AMR) AF: 0.000267 AC: 5 AN: 18704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13810

East Asian (EAS) AF: 0.00 AC: 0 AN: 31208

South Asian (SAS) AF: 0.00 AC: 0 AN: 46036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2044

European-Non Finnish (NFE) AF: 0.0000102 AC: 3 AN: 294568

Other (OTH) AF: 0.0000744 AC: 2 AN: 26884

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74328

African (AFR) AF: 0.000314 AC: 13 AN: 41422

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000263 Hom.: 0

Bravo AF: 0.0000718

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Multiple endocrine neoplasia, type 1 (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		-0.76
PromoterAI		-0.0077	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: -19
DS_DL_spliceai		0.81		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587777949; hg19: chr11-64577739;