9-21931006-A-G

Variant names:

• chr9-21931006-A-G
• rs2131048008
• ENST00000580900.5:c.814-2A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001396044.1(MTAP):​c.814-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MTAP NM_001396044.1 splice_acceptor, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.332
• Publications: 0 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]

ERVFRD-3 (HGNC:49792): (endogenous retrovirus group FRD member 3)

ENSG00000264545 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21931006-A-G is Pathogenic according to our data. Variant chr9-21931006-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 29791.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.135684). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001396044.1. 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_001396044.1		c.814-2A>G		splice_acceptor intron	N/A	NP_001382973.1	Q13126-2
	MTAP	NM_001396041.1		c.814-2A>G		splice_acceptor intron	N/A	NP_001382970.1	Q13126-3
	MTAP	NM_001396045.1		c.691-2A>G		splice_acceptor intron	N/A	NP_001382974.1	Q13126-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTAP	ENST00000580900.5	TSL:1	c.814-2A>G		splice_acceptor intron	N/A	ENSP00000463424.1	Q13126-3
	MTAP	ENST00000577563.1	TSL:1	c.148-2A>G		splice_acceptor intron	N/A	ENSP00000462082.1	J3KRN1
	ERVFRD-3	ENST00000578561.1	TSL:6	n.1550A>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 610506 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 333660

African (AFR) AF: 0.00 AC: 0 AN: 17630

American (AMR) AF: 0.00 AC: 0 AN: 43436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20786

East Asian (EAS) AF: 0.00 AC: 0 AN: 36038

South Asian (SAS) AF: 0.00 AC: 0 AN: 69338

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4124

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 348670

Other (OTH) AF: 0.00 AC: 0 AN: 32860

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Diaphyseal medullary stenosis-bone malignancy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.97
FATHMM_MKL	Benign	0.058	N
PhyloP100		0.33
GERP RS		0.22
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2131048008; hg19: chr9-21931005;