19-2177194-C-G

Variant summary

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

The NM_032482.3(DOT1L):c.82-3519C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.28 in 152,162 control chromosomes in the GnomAD database, including 7,396 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 0.28 (7396 hom., cov: 33)
• Consequence: DOT1L NM_032482.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.545

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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOT1L	NM_032482.3	c.82-3519C>G		intron_variant		ENST00000398665.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOT1L	ENST00000398665.8	c.82-3519C>G		intron_variant		1	NM_032482.3	P2
DOT1L	ENST00000452696.5	c.82-3519C>G		intron_variant		3
DOT1L	ENST00000686010.1	c.82-3519C>G		intron_variant				A2
DOT1L	ENST00000478937.3	c.69-3519C>G		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.281 AC: 42666 AN: 152044 Hom.: 7398 Cov.: 33

Gnomad AFR AF: 0.0821

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.317

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

GnomAD4 genome AF: 0.280 AC: 42646 AN: 152162 Hom.: 7396 Cov.: 33 AF XY: 0.277 AC XY: 20599 AN XY: 74402

Gnomad4 AFR AF: 0.0819

Gnomad4 AMR AF: 0.293

Gnomad4 ASJ AF: 0.357

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.318

Gnomad4 NFE AF: 0.396

Gnomad4 OTH AF: 0.313

Alfa AF: 0.349 Hom.: 5368

Bravo AF: 0.274

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.69
Dann	Benign	0.58

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: rs12982744; hg19: chr19-2177193;