9-21815438-A-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_002451.4(MTAP):c.39A>C(p.Gly13=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0004 in 1,593,858 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (1 hom.)
• Consequence: MTAP NM_002451.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.35

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 9-21815438-A-C is Benign according to our data. Variant chr9-21815438-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 366235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21815438-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BS2: High AC in GnomAd at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTAP	NM_002451.4	c.39A>C	p.Gly13=	synonymous_variant	2/8	ENST00000644715.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTAP	ENST00000644715.2	c.39A>C	p.Gly13=	synonymous_variant	2/8		NM_002451.4	P1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000278 AC: 68 AN: 244700 Hom.: 0 AF XY: 0.000311 AC XY: 41 AN XY: 131886

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.000301

Gnomad ASJ exome AF: 0.000603

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000393

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000420 AC: 606 AN: 1441720 Hom.: 1 Cov.: 28 AF XY: 0.000435 AC XY: 312 AN XY: 717354

Gnomad4 AFR exome AF: 0.0000608

Gnomad4 AMR exome AF: 0.000346

Gnomad4 ASJ exome AF: 0.000655

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000244

Gnomad4 NFE exome AF: 0.000480

Gnomad4 OTH exome AF: 0.000519

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74316

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000376 Hom.: 0

Bravo AF: 0.000219

EpiCase AF: 0.000274

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Diaphyseal medullary stenosis-bone malignancy syndrome Benign:1

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

MTAP: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	11
Dann	Benign	0.87

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: rs139020435; hg19: chr9-21815437;