rs2864419

Positions:

• chr19-2183176-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032482.3(DOT1L):​c.125+2420G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.448 in 151,928 control chromosomes in the GnomAD database, including 15,382 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 0.45 (15382 hom., cov: 31)
• Consequence: DOT1L NM_032482.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.407

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOT1L	NM_032482.3	c.125+2420G>T		intron_variant		ENST00000398665.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOT1L	ENST00000398665.8	c.125+2420G>T		intron_variant		1	NM_032482.3	P2
DOT1L	ENST00000452696.5	c.125+2420G>T		intron_variant		3
DOT1L	ENST00000686010.1	c.125+2420G>T		intron_variant				A2
DOT1L	ENST00000478937.3	c.112+2420G>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68081 AN: 151810 Hom.: 15370 Cov.: 31

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.463

Gnomad OTH AF: 0.469

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

GnomAD4 genome AF: 0.448 AC: 68122 AN: 151928 Hom.: 15382 Cov.: 31 AF XY: 0.448 AC XY: 33305 AN XY: 74272

Gnomad4 AFR AF: 0.440

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.390

Gnomad4 EAS AF: 0.473

Gnomad4 SAS AF: 0.416

Gnomad4 FIN AF: 0.457

Gnomad4 NFE AF: 0.463

Gnomad4 OTH AF: 0.465

Alfa AF: 0.463 Hom.: 22015

Bravo AF: 0.450

Asia WGS AF: 0.431 AC: 1499 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.26
DANN	Benign	0.39

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: rs2864419; hg19: chr19-2183175;