rs10965163

chr9-21854741-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002451.4(MTAP):c.561C>T(p.Arg187=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0804 in 1,614,066 control chromosomes in the GnomAD database, including 5,832 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (376 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5456 hom.)
• Consequence: MTAP NM_002451.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0730

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 9-21854741-C-T is Benign according to our data. Variant chr9-21854741-C-T is described in ClinVar as [Benign]. Clinvar id is 366244.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.073 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTAP	NM_002451.4	c.561C>T	p.Arg187=	synonymous_variant	6/8	ENST00000644715.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTAP	ENST00000644715.2	c.561C>T	p.Arg187=	synonymous_variant	6/8		NM_002451.4	P1

Frequencies

GnomAD3 genomes AF: 0.0597 AC: 9084 AN: 152164 Hom.: 376 Cov.: 33

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0712

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.0441

Gnomad FIN AF: 0.0312

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0871

Gnomad OTH AF: 0.0763

GnomAD3 exomes AF: 0.0642 AC: 16140 AN: 251234 Hom.: 669 AF XY: 0.0658 AC XY: 8931 AN XY: 135776

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.0560

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.0196

Gnomad SAS exome AF: 0.0440

Gnomad FIN exome AF: 0.0349

Gnomad NFE exome AF: 0.0860

Gnomad OTH exome AF: 0.0745

GnomAD4 exome AF: 0.0826 AC: 120694 AN: 1461784 Hom.: 5456 Cov.: 31 AF XY: 0.0818 AC XY: 59462 AN XY: 727184

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.0573

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.0487

Gnomad4 SAS exome AF: 0.0468

Gnomad4 FIN exome AF: 0.0364

Gnomad4 NFE exome AF: 0.0913

Gnomad4 OTH exome AF: 0.0758

GnomAD4 genome AF: 0.0596 AC: 9082 AN: 152282 Hom.: 376 Cov.: 33 AF XY: 0.0588 AC XY: 4375 AN XY: 74456

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.0711

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.0342

Gnomad4 SAS AF: 0.0439

Gnomad4 FIN AF: 0.0312

Gnomad4 NFE AF: 0.0871

Gnomad4 OTH AF: 0.0755

Alfa AF: 0.0849 Hom.: 1035

Bravo AF: 0.0602

Asia WGS AF: 0.0280 AC: 96 AN: 3478

EpiCase AF: 0.0924

EpiControl AF: 0.0909

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diaphyseal medullary stenosis-bone malignancy syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	7.3
Dann	Benign	0.88

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

LitVar

Other links and lift over

dbSNP: rs10965163; hg19: chr9-21854740; COSMIC: COSV66477204; COSMIC: COSV66477204;