Genetic Variant MTAP:c.120+85dupA (chr9-21815590-T-TA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_002451.4(MTAP):c.120+85dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 0)

Exomes 𝑓: 0.073 ( 23 hom. )

Consequence

MTAP
NM_002451.4 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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 -8 ACMG points.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0733 (42228/576176) while in subpopulation AFR AF = 0.124 (1525/12344). AF 95% confidence interval is 0.118. There are 23 homozygotes in GnomAdExome4. There are 22294 alleles in the male GnomAdExome4 subpopulation. Median coverage is 12. This position passed quality control check.

BS2

High AC in GnomAd4 at 502 AD gene.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.00344

AC:

503

AN:

146056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00953

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.000871

Gnomad EAS

AF:

0.000600

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00489

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000718

Gnomad OTH

AF:

0.00150

GnomAD2 exomes

AF:

0.111

AC:

9473

AN:

85622

AF XY:

0.114

show subpopulations

Gnomad AFR exome

AF:

0.164

Gnomad AMR exome

AF:

0.137

Gnomad ASJ exome

AF:

0.116

Gnomad EAS exome

AF:

0.138

Gnomad FIN exome

AF:

0.0583

Gnomad NFE exome

AF:

0.104

Gnomad OTH exome

AF:

0.107

GnomAD4 exome

AF:

0.0733

AC:

42228

AN:

576176

Hom.:

Cov.:

AF XY:

0.0727

AC XY:

22294

AN XY:

306792

show subpopulations

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

African (AFR)

AF:

0.124

AC:

1525

AN:

12344

American (AMR)

AF:

0.118

AC:

2246

AN:

19078

Ashkenazi Jewish (ASJ)

AF:

0.0827

AC:

1357

AN:

16404

East Asian (EAS)

AF:

0.102

AC:

2628

AN:

25824

South Asian (SAS)

AF:

0.0831

AC:

4149

AN:

49950

European-Finnish (FIN)

AF:

0.0619

AC:

2557

AN:

41338

Middle Eastern (MID)

AF:

0.0922

AC:

209

AN:

2268

European-Non Finnish (NFE)

AF:

0.0663

AC:

25273

AN:

380958

Other (OTH)

AF:

0.0815

AC:

2284

AN:

28012

⚠️ 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: 0.281

Heterozygous variant carriers

3495

6990

10485

13980

17475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00344

AC:

502

AN:

146114

Hom.:

Cov.:

AF XY:

0.00336

AC XY:

238

AN XY:

70754

show subpopulations

African (AFR)

AF:

0.00949

AC:

377

AN:

39742

American (AMR)

AF:

0.00177

AC:

AN:

14730

Ashkenazi Jewish (ASJ)

AF:

0.000871

AC:

AN:

3444

East Asian (EAS)

AF:

0.000601

AC:

AN:

4992

South Asian (SAS)

AF:

0.00

AC:

AN:

4588

European-Finnish (FIN)

AF:

0.00489

AC:

AN:

8588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.000718

AC:

AN:

66822

Other (OTH)

AF:

0.00149

AC:

AN:

2014

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.131

Hom.:

233

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.53

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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chr9-21815590-T-TA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over