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

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002451.4(MTAP):​c.121-76T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000888 in 1,126,370 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: MTAP NM_002451.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0880
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.88e-7 AC: 1 AN: 1126370 Hom.: 0 AF XY: 0.00000174 AC XY: 1 AN XY: 573094

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26062

American (AMR) AF: 0.00 AC: 0 AN: 39136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22694

East Asian (EAS) AF: 0.00 AC: 0 AN: 37582

South Asian (SAS) AF: 0.00 AC: 0 AN: 73618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5034

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 826250

Other (OTH) AF: 0.00 AC: 0 AN: 49194

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.37
PhyloP100		-0.088

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;