19-2170955-A-T

Variant names:

• chr19-2170955-A-T
• rs12986413
• NM_032482.3:c.81+6690A>T

Variant summary

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

The NM_032482.3(DOT1L):​c.81+6690A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.463 in 151,724 control chromosomes in the GnomAD database, including 16,358 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 (16358 hom., cov: 30)
• Consequence: DOT1L NM_032482.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.706
• Publications: 40 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.469 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOT1L	NM_032482.3	MANE Select	c.81+6690A>T		intron	N/A	NP_115871.1	Q8TEK3-2
	DOT1L	NM_001411141.1		c.81+6690A>T		intron	N/A	NP_001398070.1	A0A8I5QL06

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOT1L	ENST00000398665.8	TSL:1 MANE Select	c.81+6690A>T		intron	N/A	ENSP00000381657.3	Q8TEK3-2
	DOT1L	ENST00000686010.1		c.81+6690A>T		intron	N/A	ENSP00000510335.1	A0A8I5QL06
	DOT1L	ENST00000936177.1		c.81+6690A>T		intron	N/A	ENSP00000606236.1

Frequencies

GnomAD3 genomes AF: 0.463 AC: 70166 AN: 151606 Hom.: 16338 Cov.: 30

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.433

Gnomad AMR AF: 0.425

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.488

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

GnomAD4 genome AF: 0.463 AC: 70224 AN: 151724 Hom.: 16358 Cov.: 30 AF XY: 0.462 AC XY: 34219 AN XY: 74096

African (AFR) AF: 0.472 AC: 19527 AN: 41356

American (AMR) AF: 0.424 AC: 6469 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1403 AN: 3472

East Asian (EAS) AF: 0.472 AC: 2433 AN: 5160

South Asian (SAS) AF: 0.419 AC: 2005 AN: 4790

European-Finnish (FIN) AF: 0.446 AC: 4686 AN: 10512

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

European-Non Finnish (NFE) AF: 0.474 AC: 32155 AN: 67876

Other (OTH) AF: 0.484 AC: 1020 AN: 2108

Alfa AF: 0.469 Hom.: 2125

Bravo AF: 0.467

Asia WGS AF: 0.440 AC: 1529 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.2
DANN	Benign	0.35
PhyloP100		-0.71
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: rs12986413; hg19: chr19-2170954;