Genetic Variant NM_001370259.2:c.435C>T (chr11-64809675-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001370259.2(MEN1):c.435C>T(p.Ser145Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.0354 in 1,614,046 control chromosomes in the GnomAD database, including 1,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 89 hom., cov: 31)

Exomes 𝑓: 0.036 ( 1151 hom. )

Consequence

MEN1
NM_001370259.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 3.77

Publications

14 publications found

Variant links:

COSMIC-nc: COSV56341605

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

MEN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 11-64809675-G-A is Benign according to our data. Variant chr11-64809675-G-A is described in ClinVar as Benign. ClinVar VariationId is 96252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0267 (4070/152278) while in subpopulation NFE AF = 0.0407 (2768/68018). AF 95% confidence interval is 0.0394. There are 89 homozygotes in GnomAd4. There are 2015 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 4070 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEN1	NM_001370259.2	MANE Select	c.435C>T	p.Ser145Ser	synonymous	Exon 2 of 10	NP_001357188.2	O00255-2
MEN1	NM_001407150.1		c.435C>T	p.Ser145Ser	synonymous	Exon 2 of 11	NP_001394079.1
MEN1	NM_001370251.2		c.435C>T	p.Ser145Ser	synonymous	Exon 2 of 11	NP_001357180.2	A0A5F9ZHS3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MEN1	ENST00000450708.7	TSL:5 MANE Select	c.435C>T	p.Ser145Ser	synonymous	Exon 2 of 10	ENSP00000394933.3	O00255-2
MEN1	ENST00000312049.11	TSL:1	c.435C>T	p.Ser145Ser	synonymous	Exon 2 of 10	ENSP00000308975.6	O00255-2
MEN1	ENST00000424912.2	TSL:1	c.435C>T	p.Ser145Ser	synonymous	Exon 3 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes

AF:

0.0267

AC:

4070

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00760

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00683

Gnomad FIN

AF:

0.0655

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0407

Gnomad OTH

AF:

0.0120

GnomAD2 exomes

AF:

0.0278

AC:

6989

AN:

251364

AF XY:

0.0281

show subpopulations

Gnomad AFR exome

AF:

0.00671

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.00794

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0644

Gnomad NFE exome

AF:

0.0406

Gnomad OTH exome

AF:

0.0315

GnomAD4 exome

AF:

0.0363

AC:

53020

AN:

1461768

Hom.:

1151

Cov.:

AF XY:

0.0356

AC XY:

25866

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.00603

AC:

202

AN:

33480

American (AMR)

AF:

0.00982

AC:

439

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00716

AC:

187

AN:

26132

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.00765

AC:

660

AN:

86256

European-Finnish (FIN)

AF:

0.0634

AC:

3387

AN:

53420

Middle Eastern (MID)

AF:

0.0130

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0417

AC:

46341

AN:

1111906

Other (OTH)

AF:

0.0286

AC:

1726

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

2880

5761

8641

11522

14402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1686

3372

5058

6744

8430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0267

AC:

4070

AN:

152278

Hom.:

Cov.:

AF XY:

0.0271

AC XY:

2015

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00758

AC:

315

AN:

41556

American (AMR)

AF:

0.0114

AC:

175

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00704

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0655

AC:

695

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0407

AC:

2768

AN:

68018

Other (OTH)

AF:

0.0119

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

202

404

607

809

1011

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0312

Hom.:

Bravo

AF:

0.0213

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0339

EpiControl

AF:

0.0334

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Multiple endocrine neoplasia, type 1 (6)

not provided (5)

not specified (5)

Hereditary cancer-predisposing syndrome (2)

Hyperparathyroidism (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.87

PhyloP100

3.8

PromoterAI

-0.033

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over