rs4478653

Variant names:

• chr9-21853222-T-C
• rs4478653
• NM_002451.4:c.451-1409T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002451.4(MTAP):​c.451-1409T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 151,784 control chromosomes in the GnomAD database, including 22,802 homozygotes. 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 0.53 (22802 hom., cov: 31)
• Consequence: MTAP NM_002451.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.68
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTAP	NM_002451.4	c.451-1409T>C		intron_variant	Intron 5 of 7	ENST00000644715.2	NP_002442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTAP	ENST00000644715.2	c.451-1409T>C		intron_variant	Intron 5 of 7		NM_002451.4	ENSP00000494373.1

Frequencies

GnomAD3 genomes AF: 0.527 AC: 79908 AN: 151666 Hom.: 22752 Cov.: 31

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.525

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.739

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.397

Gnomad OTH AF: 0.492

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.527 AC: 80018 AN: 151784 Hom.: 22802 Cov.: 31 AF XY: 0.531 AC XY: 39392 AN XY: 74158

African (AFR) AF: 0.716 AC: 29610 AN: 41380

American (AMR) AF: 0.586 AC: 8936 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1452 AN: 3468

East Asian (EAS) AF: 0.738 AC: 3789 AN: 5134

South Asian (SAS) AF: 0.476 AC: 2290 AN: 4812

European-Finnish (FIN) AF: 0.510 AC: 5356 AN: 10510

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.397 AC: 26937 AN: 67932

Other (OTH) AF: 0.496 AC: 1041 AN: 2100

Alfa AF: 0.435 Hom.: 64037

Bravo AF: 0.550

Asia WGS AF: 0.614 AC: 2138 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.55
DANN	Benign	0.46
PhyloP100		-1.7
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: rs4478653; hg19: chr9-21853221;