chr9-21802470-A-G

Variant names:

• chr9-21802470-A-G
• rs2165408
• NM_002451.4:c.-279A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002451.4(MTAP):​c.-279A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 337,078 control chromosomes in the GnomAD database, including 19,376 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.56 (17329 hom., cov: 23)
  • Exomes 𝑓: 0.50 (2047 hom.)
• Consequence: MTAP NM_002451.4 upstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.155
• Publications: 4 publications found

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

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-21802470-A-G is Benign according to our data. Variant chr9-21802470-A-G is described in ClinVar as Benign. ClinVar VariationId is 1228035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.688 is higher than 0.05.

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.555 AC: 70729 AN: 127420 Hom.: 17318 Cov.: 23

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.515

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.458

Gnomad NFE AF: 0.512

Gnomad OTH AF: 0.525

GnomAD4 exome AF: 0.500 AC: 104775 AN: 209654 Hom.: 2047 AF XY: 0.499 AC XY: 54054 AN XY: 108350

African (AFR) AF: 0.510 AC: 2866 AN: 5616

American (AMR) AF: 0.507 AC: 3964 AN: 7820

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 3291 AN: 6644

East Asian (EAS) AF: 0.512 AC: 8421 AN: 16454

South Asian (SAS) AF: 0.492 AC: 7142 AN: 14526

European-Finnish (FIN) AF: 0.503 AC: 7934 AN: 15778

Middle Eastern (MID) AF: 0.496 AC: 454 AN: 916

European-Non Finnish (NFE) AF: 0.498 AC: 64198 AN: 128920

Other (OTH) AF: 0.501 AC: 6505 AN: 12980

GnomAD4 genome AF: 0.555 AC: 70751 AN: 127424 Hom.: 17329 Cov.: 23 AF XY: 0.552 AC XY: 34306 AN XY: 62156

African (AFR) AF: 0.649 AC: 20125 AN: 30994

American (AMR) AF: 0.579 AC: 7847 AN: 13554

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 1588 AN: 3082

East Asian (EAS) AF: 0.708 AC: 3414 AN: 4824

South Asian (SAS) AF: 0.403 AC: 1686 AN: 4182

European-Finnish (FIN) AF: 0.505 AC: 4079 AN: 8074

Middle Eastern (MID) AF: 0.467 AC: 113 AN: 242

European-Non Finnish (NFE) AF: 0.512 AC: 30691 AN: 59942

Other (OTH) AF: 0.528 AC: 919 AN: 1742

Alfa AF: 0.635 Hom.: 7796

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.2
DANN	Benign	0.14
PhyloP100		0.15
PromoterAI		-0.024	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs2165408; hg19: chr9-21802469; COSMIC: COSV66477332;