11-64805085-A-G

Variant names:

• chr11-64805085-A-G
• rs540012
• NM_001370259.2:c.1299T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001370259.2(MEN1):​c.1299T>C​(p.His433His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,614,144 control chromosomes in the GnomAD database, including 800,746 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72937 hom., cov: 36)
  • Exomes 𝑓: 1.0 (727809 hom.)
• Consequence: MEN1 NM_001370259.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.301
• Publications: 33 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 11-64805085-A-G is Benign according to our data. Variant chr11-64805085-A-G is described in ClinVar as Benign. ClinVar VariationId is 167288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.301 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 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.1299T>C	p.His433His	synonymous	Exon 9 of 10	NP_001357188.2	O00255-2
	MEN1	NM_001407150.1		c.1440T>C	p.His480His	synonymous	Exon 10 of 11	NP_001394079.1
	MEN1	NM_001370251.2		c.1425T>C	p.His475His	synonymous	Exon 10 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.1299T>C	p.His433His	synonymous	Exon 9 of 10	ENSP00000394933.3	O00255-2
	MEN1	ENST00000312049.11	TSL:1	c.1299T>C	p.His433His	synonymous	Exon 9 of 10	ENSP00000308975.6	O00255-2
	MEN1	ENST00000424912.2	TSL:1	c.1299T>C	p.His433His	synonymous	Exon 10 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes AF: 0.978 AC: 148864 AN: 152214 Hom.: 72884 Cov.: 36

Gnomad AFR AF: 0.923

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.993

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.984

GnomAD2 exomes AF: 0.994 AC: 249724 AN: 251190 AF XY: 0.996

Gnomad AFR exome AF: 0.919

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.998 AC: 1458581 AN: 1461812 Hom.: 727809 Cov.: 69 AF XY: 0.998 AC XY: 725854 AN XY: 727210

African (AFR) AF: 0.919 AC: 30772 AN: 33480

American (AMR) AF: 0.997 AC: 44569 AN: 44714

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26134 AN: 26134

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86244 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53364 AN: 53366

Middle Eastern (MID) AF: 0.997 AC: 5743 AN: 5760

European-Non Finnish (NFE) AF: 1.00 AC: 1111954 AN: 1112004

Other (OTH) AF: 0.995 AC: 60103 AN: 60396

GnomAD4 genome AF: 0.978 AC: 148976 AN: 152332 Hom.: 72937 Cov.: 36 AF XY: 0.978 AC XY: 72873 AN XY: 74480

African (AFR) AF: 0.923 AC: 38358 AN: 41556

American (AMR) AF: 0.993 AC: 15200 AN: 15312

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5188 AN: 5188

South Asian (SAS) AF: 1.00 AC: 4832 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68012 AN: 68024

Other (OTH) AF: 0.984 AC: 2080 AN: 2114

Alfa AF: 0.991 Hom.: 34255

Bravo AF: 0.975

Asia WGS AF: 0.995 AC: 3461 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Multiple endocrine neoplasia, type 1 (3)
-	-	2	not specified (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.0
DANN	Benign	0.54
PhyloP100		-0.30
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: rs540012; hg19: chr11-64572557; COSMIC: COSV108102490; COSMIC: COSV108102490;