NM_002451.4:c.166G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002451.4(MTAP):c.166G>A(p.Val56Ile) variant causes a missense change. The variant allele was found at a frequency of 0.407 in 1,605,850 control chromosomes in the GnomAD database, including 136,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 13300 hom., cov: 31)

Exomes 𝑓: 0.41 ( 123052 hom. )

Consequence

MTAP
NM_002451.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.67

Publications

47 publications found

Variant links:

Genes affected

MTAP (HGNC:7413): (methylthioadenosine phosphorylase) This gene encodes an enzyme that plays a major role in polyamine metabolism and is important for the salvage pathway of both adenine and methionine. The encoded enzyme is deficient in many cancers. Multiple alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Sep 2021]

MTAP Gene-Disease associations (from GenCC):

diaphyseal medullary stenosis-bone malignancy syndrome
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

MTAP links:

ENSG00000264545 (HGNC:):

ENSG00000264545 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 (MetaRNN=0.0035783052).

BP6

Variant 9-21816759-G-A is Benign according to our data. Variant chr9-21816759-G-A is described in ClinVar as [Benign]. Clinvar id is 366238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTAP	NM_002451.4 link	c.166G>A	p.Val56Ile	missense_variant	Exon 3 of 8	ENST00000644715.2	NP_002442.2	Q13126-1A0A384ME80

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTAP	ENST00000644715.2 link	c.166G>A	p.Val56Ile	missense_variant	Exon 3 of 8		NM_002451.4	ENSP00000494373.1		Q13126-1

Frequencies

GnomAD3 genomes

AF:

0.416

AC:

63154

AN:

151810

Hom.:

13290

Cov.:

show subpopulations

Gnomad AFR

AF:

0.436

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.421

Gnomad ASJ

AF:

0.386

Gnomad EAS

AF:

0.443

Gnomad SAS

AF:

0.238

Gnomad FIN

AF:

0.416

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.419

Gnomad OTH

AF:

0.394

GnomAD2 exomes

AF:

0.397

AC:

98297

AN:

247862

AF XY:

0.385

show subpopulations

Gnomad AFR exome

AF:

0.436

Gnomad AMR exome

AF:

0.416

Gnomad ASJ exome

AF:

0.379

Gnomad EAS exome

AF:

0.461

Gnomad FIN exome

AF:

0.435

Gnomad NFE exome

AF:

0.413

Gnomad OTH exome

AF:

0.385

GnomAD4 exome

AF:

0.406

AC:

591018

AN:

1453922

Hom.:

123052

Cov.:

AF XY:

0.400

AC XY:

289460

AN XY:

723284

show subpopulations

African (AFR)

AF:

0.431

AC:

14319

AN:

33212

American (AMR)

AF:

0.419

AC:

18442

AN:

44008

Ashkenazi Jewish (ASJ)

AF:

0.383

AC:

9967

AN:

26028

East Asian (EAS)

AF:

0.405

AC:

15998

AN:

39500

South Asian (SAS)

AF:

0.235

AC:

20016

AN:

85126

European-Finnish (FIN)

AF:

0.430

AC:

22757

AN:

52960

Middle Eastern (MID)

AF:

0.281

AC:

1614

AN:

5740

European-Non Finnish (NFE)

AF:

0.419

AC:

464233

AN:

1107240

Other (OTH)

AF:

0.394

AC:

23672

AN:

60108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.441

Heterozygous variant carriers

16686

33372

50059

66745

83431

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.416

AC:

63217

AN:

151928

Hom.:

13300

Cov.:

AF XY:

0.412

AC XY:

30603

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.436

AC:

18040

AN:

41420

American (AMR)

AF:

0.421

AC:

6433

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.386

AC:

1341

AN:

3470

East Asian (EAS)

AF:

0.444

AC:

2295

AN:

5174

South Asian (SAS)

AF:

0.239

AC:

1149

AN:

4812

European-Finnish (FIN)

AF:

0.416

AC:

4388

AN:

10546

Middle Eastern (MID)

AF:

0.317

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.419

AC:

28453

AN:

67926

Other (OTH)

AF:

0.398

AC:

840

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1863

3726

5588

7451

9314

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.410

Hom.:

40061

Bravo

AF:

0.421

TwinsUK

AF:

0.415

AC:

1540

ALSPAC

AF:

0.415

AC:

1601

ESP6500AA

AF:

0.435

AC:

1916

ESP6500EA

AF:

0.415

AC:

3569

ExAC

AF:

0.394

AC:

47881

Asia WGS

AF:

0.327

AC:

1138

AN:

3478

EpiCase

AF:

0.395

EpiControl

AF:

0.387

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Diaphyseal medullary stenosis-bone malignancy syndrome

Benign:3

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;T;T;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.76

.;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.2

M;.;M;M

PhyloP100

6.7

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.82

N;.;.;.

REVEL

Uncertain

0.49

Sift

Benign

0.13

T;.;.;.

Sift4G

Benign

0.13

T;T;.;T

Polyphen

0.0060

B;B;B;.

Vest4

0.10

MPC

0.11

ClinPred

0.033

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.37

gMVP

0.66

Mutation Taster

=83/17

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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NM_002451.4:c.166G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over