9-21815485-G-A

Variant names:

• chr9-21815485-G-A
• NM_002451.4:c.86G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002451.4(MTAP):​c.86G>A​(p.Arg29Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTAP NM_002451.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.96

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]

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTAP	NM_002451.4	c.86G>A	p.Arg29Lys	missense_variant	Exon 2 of 8	ENST00000644715.2	NP_002442.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTAP	ENST00000644715.2	c.86G>A	p.Arg29Lys	missense_variant	Exon 2 of 8		NM_002451.4	ENSP00000494373.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.86G>A (p.R29K) alteration is located in exon 2 (coding exon 2) of the MTAP gene. This alteration results from a G to A substitution at nucleotide position 86, causing the arginine (R) at amino acid position 29 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T;T;T;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;L;L
PhyloP100		9.0
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.5	N;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.48	T;.;.;.
Sift4G	Benign	0.83	T;T;.;T
Polyphen		0.11	B;P;B;.
Vest4		0.72
MutPred		0.49		.;Gain of ubiquitination at R46 (P = 0.0198);.;.;
MVP		0.64
MPC		0.53
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.86
Mutation Taster		=23/77	disease causing

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

Publications

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Other links and lift over

hg19: chr9-21815484; COSMIC: COSV66477101; COSMIC: COSV66477101;