rs4977746

Variant names:

• chr9-21920347-T-C
• rs4977746
• ENST00000580900.5:c.814-10661T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000580900.5(MTAP):​c.814-10661T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 152,032 control chromosomes in the GnomAD database, including 14,496 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.38 (14496 hom., cov: 31)
• Consequence: MTAP ENST00000580900.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.96
• Publications: 3 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: Genomics England PanelApp, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTAP	NM_001396044.1	c.814-10661T>C		intron_variant	Intron 7 of 9		NP_001382973.1
MTAP	NM_001396041.1	c.814-10661T>C		intron_variant	Intron 7 of 7		NP_001382970.1
MTAP	NM_001396045.1	c.691-10661T>C		intron_variant	Intron 6 of 8		NP_001382974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTAP	ENST00000580900.5	c.814-10661T>C		intron_variant	Intron 7 of 7	1		ENSP00000463424.1
MTAP	ENST00000577563.1	c.148-10661T>C		intron_variant	Intron 1 of 1	1		ENSP00000462082.1
ENSG00000264545	ENST00000404796.3	n.460+102145T>C		intron_variant	Intron 4 of 4	5

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57809 AN: 151912 Hom.: 14452 Cov.: 31

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.199

Gnomad OTH AF: 0.349

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.381 AC: 57923 AN: 152032 Hom.: 14496 Cov.: 31 AF XY: 0.385 AC XY: 28573 AN XY: 74288

African (AFR) AF: 0.688 AC: 28537 AN: 41464

American (AMR) AF: 0.412 AC: 6297 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 822 AN: 3470

East Asian (EAS) AF: 0.568 AC: 2927 AN: 5152

South Asian (SAS) AF: 0.344 AC: 1658 AN: 4816

European-Finnish (FIN) AF: 0.284 AC: 3004 AN: 10560

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.199 AC: 13538 AN: 67980

Other (OTH) AF: 0.352 AC: 745 AN: 2114

Alfa AF: 0.257 Hom.: 27498

Bravo AF: 0.409

Asia WGS AF: 0.476 AC: 1656 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.4
DANN	Benign	0.40
PhyloP100		-2.0
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: rs4977746; hg19: chr9-21920346; COSMIC: COSV68684360;