9-21816647-A-G

Variant names:

• chr9-21816647-A-G
• rs7023474
• NM_002451.4:c.121-67A>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.121-67A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 1,408,308 control chromosomes in the GnomAD database, including 223,780 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31459 hom., cov: 32)
  • Exomes 𝑓: 0.55 (192321 hom.)
• Consequence: MTAP NM_002451.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.622
• Publications: 6 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: Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000264545 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 9-21816647-A-G is Benign according to our data. Variant chr9-21816647-A-G is described in ClinVar as Benign. ClinVar VariationId is 1239449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.809 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTAP	NM_002451.4	MANE Select	c.121-67A>G		intron	N/A	NP_002442.2
	MTAP	NM_001396044.1		c.121-67A>G		intron	N/A	NP_001382973.1
	MTAP	NM_001396041.1		c.121-67A>G		intron	N/A	NP_001382970.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTAP	ENST00000644715.2	MANE Select	c.121-67A>G		intron	N/A	ENSP00000494373.1
	MTAP	ENST00000580900.5	TSL:1	c.121-67A>G		intron	N/A	ENSP00000463424.1
	MTAP	ENST00000580718.1	TSL:1	n.121-67A>G		intron	N/A	ENSP00000464616.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 96005 AN: 151874 Hom.: 31401 Cov.: 32

Gnomad AFR AF: 0.816

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.581

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.414

Gnomad FIN AF: 0.543

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.549

Gnomad OTH AF: 0.603

GnomAD4 exome AF: 0.547 AC: 687281 AN: 1256316 Hom.: 192321 AF XY: 0.540 AC XY: 342013 AN XY: 632976

African (AFR) AF: 0.821 AC: 23725 AN: 28912

American (AMR) AF: 0.665 AC: 26406 AN: 39728

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 13639 AN: 23886

East Asian (EAS) AF: 0.636 AC: 24254 AN: 38150

South Asian (SAS) AF: 0.405 AC: 31281 AN: 77154

European-Finnish (FIN) AF: 0.560 AC: 27080 AN: 48350

Middle Eastern (MID) AF: 0.527 AC: 2770 AN: 5258

European-Non Finnish (NFE) AF: 0.540 AC: 508018 AN: 941520

Other (OTH) AF: 0.564 AC: 30108 AN: 53358

GnomAD4 genome AF: 0.632 AC: 96126 AN: 151992 Hom.: 31459 Cov.: 32 AF XY: 0.627 AC XY: 46581 AN XY: 74272

African (AFR) AF: 0.816 AC: 33853 AN: 41490

American (AMR) AF: 0.628 AC: 9598 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 2016 AN: 3472

East Asian (EAS) AF: 0.708 AC: 3658 AN: 5164

South Asian (SAS) AF: 0.416 AC: 1999 AN: 4810

European-Finnish (FIN) AF: 0.543 AC: 5724 AN: 10538

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.549 AC: 37314 AN: 67928

Other (OTH) AF: 0.604 AC: 1275 AN: 2110

Alfa AF: 0.583 Hom.: 4705

Bravo AF: 0.655

Asia WGS AF: 0.581 AC: 2020 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.3
DANN	Benign	0.77
PhyloP100		0.62
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7023474; hg19: chr9-21816646; COSMIC: COSV66477127; COSMIC: COSV66477127;