9-21853340-A-G

Variant names:

• chr9-21853340-A-G
• rs10118757
• NM_002451.4:c.451-1291A>G

Variant summary

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

The NM_002451.4(MTAP):​c.451-1291A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 152,048 control chromosomes in the GnomAD database, including 6,690 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 0.25 (6690 hom., cov: 32)
• Consequence: MTAP NM_002451.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• Publications: 7 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTAP	NM_002451.4	c.451-1291A>G		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.451-1291A>G		intron_variant	Intron 5 of 7		NM_002451.4	ENSP00000494373.1

Frequencies

GnomAD3 genomes AF: 0.254 AC: 38609 AN: 151930 Hom.: 6676 Cov.: 32

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.213

Gnomad ASJ AF: 0.176

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.206

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.235

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

GnomAD4 genome AF: 0.254 AC: 38656 AN: 152048 Hom.: 6690 Cov.: 32 AF XY: 0.254 AC XY: 18888 AN XY: 74348

African (AFR) AF: 0.490 AC: 20289 AN: 41406

American (AMR) AF: 0.213 AC: 3249 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 611 AN: 3472

East Asian (EAS) AF: 0.269 AC: 1391 AN: 5176

South Asian (SAS) AF: 0.206 AC: 993 AN: 4822

European-Finnish (FIN) AF: 0.192 AC: 2033 AN: 10590

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9232 AN: 68006

Other (OTH) AF: 0.232 AC: 490 AN: 2108

Alfa AF: 0.114 Hom.: 295

Bravo AF: 0.270

Asia WGS AF: 0.263 AC: 916 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.3
DANN	Benign	0.84
PhyloP100		1.4
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: rs10118757; hg19: chr9-21853339;