Genetic Variant MTAP:c.-279A>T (chr9-21802470-A-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002451.4(MTAP):c.-279A>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 339,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000031 ( 0 hom., cov: 23)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MTAP
NM_002451.4 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.155

Publications

4 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp, Orphanet

MTAP links:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002451.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MTAP	NM_002451.4	MANE Select	c.-279A>T	upstream_gene	N/A	NP_002442.2
MTAP	NM_001396044.1		c.-279A>T	upstream_gene	N/A	NP_001382973.1	Q13126-2
MTAP	NM_001396041.1		c.-279A>T	upstream_gene	N/A	NP_001382970.1	Q13126-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MTAP	ENST00000644715.2	MANE Select	c.-279A>T	upstream_gene	N/A	ENSP00000494373.1	Q13126-1
MTAP	ENST00000580900.5	TSL:1	c.-279A>T	upstream_gene	N/A	ENSP00000463424.1	Q13126-3
MTAP	ENST00000580718.1	TSL:1	n.-279A>T	upstream_gene	N/A	ENSP00000464616.1	J3QSB7

Frequencies

GnomAD3 genomes

AF:

0.0000313

AC:

AN:

127716

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000322

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000619

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000189

AC:

AN:

212056

Hom.:

AF XY:

0.0000365

AC XY:

AN XY:

109516

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

5726

American (AMR)

AF:

0.00

AC:

AN:

7854

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

6710

East Asian (EAS)

AF:

0.0000601

AC:

AN:

16632

South Asian (SAS)

AF:

0.00

AC:

AN:

14698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15922

Middle Eastern (MID)

AF:

0.00

AC:

AN:

922

European-Non Finnish (NFE)

AF:

0.0000230

AC:

AN:

130466

Other (OTH)

AF:

0.00

AC:

AN:

13126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000164189), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.362

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000313

AC:

AN:

127720

Hom.:

Cov.:

AF XY:

0.0000321

AC XY:

AN XY:

62302

show subpopulations

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

African (AFR)

AF:

0.0000322

AC:

AN:

31072

American (AMR)

AF:

0.00

AC:

AN:

13592

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3086

East Asian (EAS)

AF:

0.000621

AC:

AN:

4834

South Asian (SAS)

AF:

0.00

AC:

AN:

4190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

242

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

60066

Other (OTH)

AF:

0.00

AC:

AN:

1746

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.263

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

7796

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.7

(source)

DANN

Benign

0.17

PhyloP100

0.15

PromoterAI

0.024

Neutral

(source)

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over