NM_002451.4:c.121-76T>C

Variant names:

• chr9-21816638-T-C
• rs10114559
• NM_002451.4:c.121-76T>C

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.121-76T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 1,272,456 control chromosomes in the GnomAD database, including 106,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10828 hom., cov: 32)
  • Exomes 𝑓: 0.40 (95545 hom.)
• Consequence: MTAP NM_002451.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0880
• Publications: 8 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 9-21816638-T-C is Benign according to our data. Variant chr9-21816638-T-C is described in ClinVar as [Benign]. Clinvar id is 1258921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTAP	NM_002451.4	c.121-76T>C		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.121-76T>C		intron_variant	Intron 2 of 7		NM_002451.4	ENSP00000494373.1

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54824 AN: 151890 Hom.: 10823 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.415

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.338

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.364

GnomAD4 exome AF: 0.405 AC: 453757 AN: 1120448 Hom.: 95545 AF XY: 0.400 AC XY: 227793 AN XY: 570052

African (AFR) AF: 0.183 AC: 4755 AN: 25986

American (AMR) AF: 0.404 AC: 15715 AN: 38904

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 8995 AN: 22582

East Asian (EAS) AF: 0.399 AC: 14943 AN: 37432

South Asian (SAS) AF: 0.234 AC: 17114 AN: 73228

European-Finnish (FIN) AF: 0.431 AC: 20081 AN: 46592

Middle Eastern (MID) AF: 0.299 AC: 1496 AN: 5008

European-Non Finnish (NFE) AF: 0.428 AC: 351677 AN: 821758

Other (OTH) AF: 0.388 AC: 18981 AN: 48958

GnomAD4 genome AF: 0.361 AC: 54868 AN: 152008 Hom.: 10828 Cov.: 32 AF XY: 0.360 AC XY: 26720 AN XY: 74296

African (AFR) AF: 0.196 AC: 8114 AN: 41498

American (AMR) AF: 0.415 AC: 6344 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1436 AN: 3470

East Asian (EAS) AF: 0.444 AC: 2288 AN: 5158

South Asian (SAS) AF: 0.244 AC: 1179 AN: 4824

European-Finnish (FIN) AF: 0.421 AC: 4438 AN: 10544

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.441 AC: 29974 AN: 67920

Other (OTH) AF: 0.368 AC: 776 AN: 2110

Alfa AF: 0.395 Hom.: 3168

Bravo AF: 0.357

Asia WGS AF: 0.318 AC: 1103 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	1.9
DANN	Benign	0.52
PhyloP100		-0.088
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: rs10114559; hg19: chr9-21816637; COSMIC: COSV66477123; COSMIC: COSV66477123;