19-2194897-T-C

Variant names:

• chr19-2194897-T-C
• rs2269879
• NM_032482.3:c.651+320T>C

Variant summary

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

The NM_032482.3(DOT1L):​c.651+320T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.841 in 152,144 control chromosomes in the GnomAD database, including 54,620 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 0.84 (54620 hom., cov: 32)
• Consequence: DOT1L NM_032482.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.46
• Publications: 12 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=-1.03).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032482.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOT1L	NM_032482.3	MANE Select	c.651+320T>C		intron	N/A	NP_115871.1
	DOT1L	NM_001411141.1		c.651+320T>C		intron	N/A	NP_001398070.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOT1L	ENST00000398665.8	TSL:1 MANE Select	c.651+320T>C		intron	N/A	ENSP00000381657.3
	DOT1L	ENST00000686010.1		c.651+320T>C		intron	N/A	ENSP00000510335.1
	DOT1L	ENST00000452696.5	TSL:3	c.579+320T>C		intron	N/A	ENSP00000404284.1

Frequencies

GnomAD3 genomes AF: 0.841 AC: 127915 AN: 152026 Hom.: 54597 Cov.: 32

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.815

Gnomad ASJ AF: 0.915

Gnomad EAS AF: 0.788

Gnomad SAS AF: 0.886

Gnomad FIN AF: 0.930

Gnomad MID AF: 0.867

Gnomad NFE AF: 0.915

Gnomad OTH AF: 0.866

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

GnomAD4 genome AF: 0.841 AC: 127988 AN: 152144 Hom.: 54620 Cov.: 32 AF XY: 0.844 AC XY: 62747 AN XY: 74386

African (AFR) AF: 0.700 AC: 29043 AN: 41486

American (AMR) AF: 0.815 AC: 12454 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.915 AC: 3174 AN: 3470

East Asian (EAS) AF: 0.788 AC: 4053 AN: 5142

South Asian (SAS) AF: 0.886 AC: 4274 AN: 4826

European-Finnish (FIN) AF: 0.930 AC: 9869 AN: 10612

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.915 AC: 62230 AN: 68004

Other (OTH) AF: 0.858 AC: 1811 AN: 2110

Alfa AF: 0.886 Hom.: 208901

Bravo AF: 0.825

Asia WGS AF: 0.786 AC: 2737 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.17
DANN	Benign	0.21
PhyloP100		-2.5
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4
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: rs2269879; hg19: chr19-2194896;