Genetic Variant NM_001370259.2:c.-22C>A (chr11-64810131-G-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001370259.2(MEN1):c.-22C>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 885,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0017 ( 0 hom. )

Consequence

MEN1
NM_001370259.2 splice_region

Scores

Splicing: ADA: 0.006878

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 2.24

Publications

0 publications found

Variant links:

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: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 11-64810131-G-T is Benign according to our data. Variant chr11-64810131-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241793.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00071 (103/145168) while in subpopulation NFE AF = 0.00121 (80/66344). AF 95% confidence interval is 0.000993. There are 0 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High AC in GnomAd4 at 103 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	Effect	Exon Rank	Protein	UniProt
MEN1	NM_001370259.2	MANE Select	c.-22C>A	splice_region	Exon 2 of 10	NP_001357188.2	O00255-2
MEN1	NM_001370259.2	MANE Select	c.-22C>A	5_prime_UTR	Exon 2 of 10	NP_001357188.2	O00255-2
MEN1	NM_001407150.1		c.-22C>A	splice_region	Exon 2 of 11	NP_001394079.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MEN1	ENST00000450708.7	TSL:5 MANE Select	c.-22C>A	splice_region	Exon 2 of 10	ENSP00000394933.3	O00255-2
MEN1	ENST00000312049.11	TSL:1	c.-22C>A	splice_region	Exon 2 of 10	ENSP00000308975.6	O00255-2
MEN1	ENST00000424912.2	TSL:1	c.-22C>A	splice_region	Exon 3 of 11	ENSP00000388016.2	O00255-2

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

103

AN:

145100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000308

Gnomad AMI

AF:

0.00452

Gnomad AMR

AF:

0.000409

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000109

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000654

AC:

AN:

122410

AF XY:

0.000699

show subpopulations

Gnomad AFR exome

AF:

0.000302

Gnomad AMR exome

AF:

0.000268

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000826

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.00166

AC:

1230

AN:

740484

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

594

AN XY:

370200

show subpopulations

African (AFR)

AF:

0.000455

AC:

AN:

17570

American (AMR)

AF:

0.000489

AC:

AN:

28620

Ashkenazi Jewish (ASJ)

AF:

0.0000708

AC:

AN:

14116

East Asian (EAS)

AF:

0.0000443

AC:

AN:

22592

South Asian (SAS)

AF:

0.00

AC:

AN:

59702

European-Finnish (FIN)

AF:

0.00163

AC:

AN:

14122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2242

European-Non Finnish (NFE)

AF:

0.00209

AC:

1156

AN:

551810

Other (OTH)

AF:

0.000909

AC:

AN:

29710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

116

173

231

289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000710

AC:

103

AN:

145168

Hom.:

Cov.:

AF XY:

0.000666

AC XY:

AN XY:

70586

show subpopulations

African (AFR)

AF:

0.000307

AC:

AN:

39102

American (AMR)

AF:

0.000408

AC:

AN:

14688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3412

East Asian (EAS)

AF:

0.00

AC:

AN:

4824

South Asian (SAS)

AF:

0.00

AC:

AN:

4444

European-Finnish (FIN)

AF:

0.000109

AC:

AN:

9154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00121

AC:

AN:

66344

Other (OTH)

AF:

0.00

AC:

AN:

2030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00102

Hom.:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Multiple endocrine neoplasia, type 1 (2)

not provided (2)

Hereditary cancer-predisposing syndrome (1)

MEN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

2.2

PromoterAI

-0.19

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.2

Mutation Taster

=293/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0069

dbscSNV1_RF

Benign

0.040

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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