Genetic Variant MTAP:c.120+84_120+85dupAA (chr9-21815590-T-TAA) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_002451.4(MTAP):c.120+84_120+85dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.18 ( 2885 hom., cov: 0)

Exomes 𝑓: 0.36 ( 454 hom. )

Consequence

MTAP
NM_002451.4 intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.529

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 links:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 9-21815590-T-TAA is Benign according to our data. Variant chr9-21815590-T-TAA is described in ClinVar as [Benign]. Clinvar id is 1276709.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.294 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTAP	NM_002451.4 link	c.120+84_120+85dupAA		intron_variant	Intron 2 of 7	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.120+84_120+85dupAA		intron_variant	Intron 2 of 7		NM_002451.4	ENSP00000494373.1		Q13126-1

Frequencies

GnomAD3 genomes

AF:

0.183

AC:

26637

AN:

145926

Hom.:

2881

Cov.:

show subpopulations

Gnomad AFR

AF:

0.298

Gnomad AMI

AF:

0.330

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.162

Gnomad EAS

AF:

0.273

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.148

Gnomad MID

AF:

0.218

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.172

GnomAD2 exomes

AF:

0.414

AC:

35446

AN:

85622

AF XY:

0.413

show subpopulations

Gnomad AFR exome

AF:

0.421

Gnomad AMR exome

AF:

0.398

Gnomad ASJ exome

AF:

0.412

Gnomad EAS exome

AF:

0.419

Gnomad FIN exome

AF:

0.456

Gnomad NFE exome

AF:

0.402

Gnomad OTH exome

AF:

0.404

GnomAD4 exome

AF:

0.364

AC:

212659

AN:

584196

Hom.:

454

Cov.:

AF XY:

0.368

AC XY:

114337

AN XY:

310646

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.382

AC:

4846

AN:

12678

American (AMR)

AF:

0.376

AC:

7339

AN:

19504

Ashkenazi Jewish (ASJ)

AF:

0.374

AC:

6268

AN:

16742

East Asian (EAS)

AF:

0.394

AC:

10411

AN:

26410

South Asian (SAS)

AF:

0.400

AC:

20264

AN:

50620

European-Finnish (FIN)

AF:

0.403

AC:

16661

AN:

41294

Middle Eastern (MID)

AF:

0.379

AC:

866

AN:

2284

European-Non Finnish (NFE)

AF:

0.351

AC:

135544

AN:

386228

Other (OTH)

AF:

0.368

AC:

10460

AN:

28436

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.355

Heterozygous variant carriers

11905

23810

35716

47621

59526

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.183

AC:

26662

AN:

145980

Hom.:

2885

Cov.:

AF XY:

0.184

AC XY:

13022

AN XY:

70670

show subpopulations

African (AFR)

AF:

0.299

AC:

11862

AN:

39720

American (AMR)

AF:

0.183

AC:

2691

AN:

14706

Ashkenazi Jewish (ASJ)

AF:

0.162

AC:

557

AN:

3432

East Asian (EAS)

AF:

0.273

AC:

1361

AN:

4990

South Asian (SAS)

AF:

0.164

AC:

751

AN:

4580

European-Finnish (FIN)

AF:

0.148

AC:

1272

AN:

8574

Middle Eastern (MID)

AF:

0.208

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.112

AC:

7465

AN:

66772

Other (OTH)

AF:

0.171

AC:

345

AN:

2016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

968

1936

2903

3871

4839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.357

Hom.:

233

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 20, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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9-21815590-T-TAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over