NM_002451.4:c.121-140G>A

Variant names:

• chr9-21816574-G-A
• rs7023680
• NM_002451.4:c.121-140G>A

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.121-140G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 671,772 control chromosomes in the GnomAD database, including 108,827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31474 hom., cov: 32)
  • Exomes 𝑓: 0.54 (77353 hom.)
• Consequence: MTAP NM_002451.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0550
• Publications: 3 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=-0.86).
• BP6: Variant 9-21816574-G-A is Benign according to our data. Variant chr9-21816574-G-A is described in ClinVar as [Benign]. Clinvar id is 1230723.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTAP	NM_002451.4	c.121-140G>A		intron_variant	Intron 2 of 7	ENST00000644715.2	NP_002442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTAP	ENST00000644715.2	c.121-140G>A		intron_variant	Intron 2 of 7		NM_002451.4	ENSP00000494373.1

Frequencies

GnomAD3 genomes AF: 0.632 AC: 96032 AN: 151884 Hom.: 31416 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: 0.415

Gnomad FIN AF: 0.544

Gnomad MID AF: 0.576

Gnomad NFE AF: 0.550

Gnomad OTH AF: 0.604

GnomAD4 exome AF: 0.540 AC: 280577 AN: 519770 Hom.: 77353 AF XY: 0.530 AC XY: 145803 AN XY: 274892

African (AFR) AF: 0.809 AC: 10351 AN: 12798

American (AMR) AF: 0.647 AC: 13440 AN: 20774

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 8019 AN: 14082

East Asian (EAS) AF: 0.613 AC: 19166 AN: 31288

South Asian (SAS) AF: 0.388 AC: 16030 AN: 41360

European-Finnish (FIN) AF: 0.553 AC: 18728 AN: 33886

Middle Eastern (MID) AF: 0.524 AC: 1500 AN: 2862

European-Non Finnish (NFE) AF: 0.531 AC: 177537 AN: 334638

Other (OTH) AF: 0.563 AC: 15806 AN: 28082

GnomAD4 genome AF: 0.633 AC: 96153 AN: 152002 Hom.: 31474 Cov.: 32 AF XY: 0.627 AC XY: 46620 AN XY: 74300

African (AFR) AF: 0.816 AC: 33837 AN: 41468

American (AMR) AF: 0.629 AC: 9606 AN: 15282

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

East Asian (EAS) AF: 0.708 AC: 3662 AN: 5170

South Asian (SAS) AF: 0.416 AC: 2002 AN: 4810

European-Finnish (FIN) AF: 0.544 AC: 5734 AN: 10544

Middle Eastern (MID) AF: 0.589 AC: 172 AN: 292

European-Non Finnish (NFE) AF: 0.549 AC: 37329 AN: 67940

Other (OTH) AF: 0.605 AC: 1279 AN: 2114

Alfa AF: 0.574 Hom.: 11104

Bravo AF: 0.655

Asia WGS AF: 0.581 AC: 2021 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

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.4
DANN	Benign	0.53
PhyloP100		-0.055
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: rs7023680; hg19: chr9-21816573;