9-21816759-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002451.4(MTAP):c.166G>A(p.Val56Ile) variant causes a missense change. The variant allele was found at a frequency of 0.407 in 1,605,850 control chromosomes in the GnomAD database, including 136,352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13300 hom., cov: 31)
  • Exomes 𝑓: 0.41 (123052 hom.)
• Consequence: MTAP NM_002451.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.67

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035783052).
• BP6: Variant 9-21816759-G-A is Benign according to our data. Variant chr9-21816759-G-A is described in ClinVar as [Benign]. Clinvar id is 366238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTAP	NM_002451.4	c.166G>A	p.Val56Ile	missense_variant	3/8	ENST00000644715.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTAP	ENST00000644715.2	c.166G>A	p.Val56Ile	missense_variant	3/8		NM_002451.4	P1

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63154 AN: 151810 Hom.: 13290 Cov.: 31

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.443

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.416

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.419

Gnomad OTH AF: 0.394

GnomAD3 exomes AF: 0.397 AC: 98297 AN: 247862 Hom.: 20353 AF XY: 0.385 AC XY: 51560 AN XY: 134030

Gnomad AFR exome AF: 0.436

Gnomad AMR exome AF: 0.416

Gnomad ASJ exome AF: 0.379

Gnomad EAS exome AF: 0.461

Gnomad SAS exome AF: 0.233

Gnomad FIN exome AF: 0.435

Gnomad NFE exome AF: 0.413

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.406 AC: 591018 AN: 1453922 Hom.: 123052 Cov.: 32 AF XY: 0.400 AC XY: 289460 AN XY: 723284

Gnomad4 AFR exome AF: 0.431

Gnomad4 AMR exome AF: 0.419

Gnomad4 ASJ exome AF: 0.383

Gnomad4 EAS exome AF: 0.405

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.430

Gnomad4 NFE exome AF: 0.419

Gnomad4 OTH exome AF: 0.394

GnomAD4 genome AF: 0.416 AC: 63217 AN: 151928 Hom.: 13300 Cov.: 31 AF XY: 0.412 AC XY: 30603 AN XY: 74238

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.421

Gnomad4 ASJ AF: 0.386

Gnomad4 EAS AF: 0.444

Gnomad4 SAS AF: 0.239

Gnomad4 FIN AF: 0.416

Gnomad4 NFE AF: 0.419

Gnomad4 OTH AF: 0.398

Alfa AF: 0.408 Hom.: 27887

Bravo AF: 0.421

TwinsUK AF: 0.415 AC: 1540

ALSPAC AF: 0.415 AC: 1601

ESP6500AA AF: 0.435 AC: 1916

ESP6500EA AF: 0.415 AC: 3569

ExAC AF: 0.394 AC: 47881

Asia WGS AF: 0.327 AC: 1138 AN: 3478

EpiCase AF: 0.395

EpiControl AF: 0.387

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diaphyseal medullary stenosis-bone malignancy syndrome Benign:3

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	Mendelics	May 28, 2019	- -
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

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0036	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;.;M;M
MutationTaster	Benign	1.1e-10	P;P;P
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.82	N;.;.;.
REVEL	Uncertain	0.49
Sift	Benign	0.13	T;.;.;.
Sift4G	Benign	0.13	T;T;.;T
Polyphen		0.0060	B;B;B;.
Vest4		0.10
MPC		0.11
ClinPred		0.033	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7023954; hg19: chr9-21816758; COSMIC: COSV66477132; COSMIC: COSV66477132;