19-2177194-C-G

Variant names:

• chr19-2177194-C-G
• rs12982744
• NM_032482.3:c.82-3519C>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.82-3519C>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
• Publications: 70 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=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.392 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.82-3519C>G		intron	N/A	NP_115871.1	Q8TEK3-2
	DOT1L	NM_001411141.1		c.82-3519C>G		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.82-3519C>G		intron	N/A	ENSP00000381657.3	Q8TEK3-2
	DOT1L	ENST00000686010.1		c.82-3519C>G		intron	N/A	ENSP00000510335.1	A0A8I5QL06
	DOT1L	ENST00000936177.1		c.82-3519C>G		intron	N/A	ENSP00000606236.1

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

African (AFR) AF: 0.0819 AC: 3403 AN: 41542

American (AMR) AF: 0.293 AC: 4476 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.357 AC: 1240 AN: 3470

East Asian (EAS) AF: 0.201 AC: 1041 AN: 5174

South Asian (SAS) AF: 0.222 AC: 1074 AN: 4830

European-Finnish (FIN) AF: 0.318 AC: 3368 AN: 10582

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.396 AC: 26934 AN: 67966

Other (OTH) AF: 0.313 AC: 659 AN: 2106

Alfa AF: 0.349 Hom.: 5368

Bravo AF: 0.274

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.69
DANN	Benign	0.58
PhyloP100		0.55
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: rs12982744; hg19: chr19-2177193;