rs10965163

Variant names:

• chr9-21854741-C-T
• rs10965163
• NM_002451.4:c.561C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002451.4(MTAP):​c.561C>T​(p.Arg187Arg) 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:4
• Conservation: PhyloP100: -0.0730
• Publications: 17 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: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp, Orphanet

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002451.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTAP	NM_002451.4	MANE Select	c.561C>T	p.Arg187Arg	synonymous	Exon 6 of 8	NP_002442.2
	MTAP	NM_001396044.1		c.561C>T	p.Arg187Arg	synonymous	Exon 6 of 10	NP_001382973.1	Q13126-2
	MTAP	NM_001396041.1		c.561C>T	p.Arg187Arg	synonymous	Exon 6 of 8	NP_001382970.1	Q13126-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTAP	ENST00000644715.2	MANE Select	c.561C>T	p.Arg187Arg	synonymous	Exon 6 of 8	ENSP00000494373.1	Q13126-1
	MTAP	ENST00000580900.5	TSL:1	c.561C>T	p.Arg187Arg	synonymous	Exon 6 of 8	ENSP00000463424.1	Q13126-3
	MTAP	ENST00000577563.1	TSL:1	c.18C>T	p.Arg6Arg	synonymous	Exon 1 of 2	ENSP00000462082.1	J3KRN1

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

GnomAD2 exomes AF: 0.0642 AC: 16140 AN: 251234 AF XY: 0.0658

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 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

African (AFR) AF: 0.0140 AC: 468 AN: 33474

American (AMR) AF: 0.0573 AC: 2562 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 3263 AN: 26136

East Asian (EAS) AF: 0.0487 AC: 1932 AN: 39700

South Asian (SAS) AF: 0.0468 AC: 4034 AN: 86254

European-Finnish (FIN) AF: 0.0364 AC: 1943 AN: 53416

Middle Eastern (MID) AF: 0.0706 AC: 407 AN: 5766

European-Non Finnish (NFE) AF: 0.0913 AC: 101505 AN: 1111928

Other (OTH) AF: 0.0758 AC: 4580 AN: 60394

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

African (AFR) AF: 0.0169 AC: 701 AN: 41570

American (AMR) AF: 0.0711 AC: 1086 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 453 AN: 3472

East Asian (EAS) AF: 0.0342 AC: 177 AN: 5182

South Asian (SAS) AF: 0.0439 AC: 212 AN: 4830

European-Finnish (FIN) AF: 0.0312 AC: 331 AN: 10612

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0871 AC: 5925 AN: 68022

Other (OTH) AF: 0.0755 AC: 159 AN: 2106

Alfa AF: 0.0827 Hom.: 1278

Bravo AF: 0.0602

Asia WGS AF: 0.0280 AC: 96 AN: 3478

EpiCase AF: 0.0924

EpiControl AF: 0.0909

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Diaphyseal medullary stenosis-bone malignancy syndrome (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.3
DANN	Benign	0.88
PhyloP100		-0.073
PromoterAI		0.022	Neutral
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: rs10965163; hg19: chr9-21854740; COSMIC: COSV66477204; COSMIC: COSV66477204;