19-2176587-A-G

Variant names:

• chr19-2176587-A-G
• rs12459350
• NM_032482.3:c.82-4126A>G

Variant summary

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

The NM_032482.3(DOT1L):​c.82-4126A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 152,118 control chromosomes in the GnomAD database, including 16,458 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 0.46 (16458 hom., cov: 32)
• Consequence: DOT1L NM_032482.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.533
• Publications: 19 publications found

Genes affected

DOT1L (HGNC:24948): (DOT1 like histone lysine methyltransferase) The protein encoded by this gene is a histone methyltransferase that methylates lysine-79 of histone H3. It is inactive against free core histones, but shows significant histone methyltransferase activity against nucleosomes. [provided by RefSeq, Aug 2011]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOT1L	NM_032482.3	c.82-4126A>G		intron_variant	Intron 1 of 27	ENST00000398665.8	NP_115871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOT1L	ENST00000398665.8	c.82-4126A>G		intron_variant	Intron 1 of 27	1	NM_032482.3	ENSP00000381657.3
DOT1L	ENST00000686010.1	c.82-4126A>G		intron_variant	Intron 1 of 27			ENSP00000510335.1
DOT1L	ENST00000452696.5	c.82-4126A>G		intron_variant	Intron 1 of 7	3		ENSP00000404284.1
DOT1L	ENST00000478937.3	n.67-4126A>G		intron_variant	Intron 1 of 5	3		ENSP00000484015.1

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70460 AN: 152000 Hom.: 16439 Cov.: 32

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.487

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

GnomAD4 genome AF: 0.464 AC: 70518 AN: 152118 Hom.: 16458 Cov.: 32 AF XY: 0.462 AC XY: 34372 AN XY: 74344

African (AFR) AF: 0.474 AC: 19666 AN: 41498

American (AMR) AF: 0.425 AC: 6500 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1445 AN: 3472

East Asian (EAS) AF: 0.471 AC: 2430 AN: 5158

South Asian (SAS) AF: 0.418 AC: 2016 AN: 4824

European-Finnish (FIN) AF: 0.445 AC: 4711 AN: 10582

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32203 AN: 67980

Other (OTH) AF: 0.482 AC: 1017 AN: 2108

Alfa AF: 0.476 Hom.: 24382

Bravo AF: 0.467

Asia WGS AF: 0.438 AC: 1523 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.6
DANN	Benign	0.41
PhyloP100		-0.53
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: rs12459350; hg19: chr19-2176586; COSMIC: COSV67109054;