19-2185890-C-T

Variant names:

• chr19-2185890-C-T
• NM_032482.3:c.161C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_032482.3(DOT1L):​c.161C>T​(p.Ala54Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A54T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DOT1L NM_032482.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.95
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.161C>T	p.Ala54Val	missense	Exon 3 of 28	NP_115871.1	Q8TEK3-2
	DOT1L	NM_001411141.1		c.161C>T	p.Ala54Val	missense	Exon 3 of 28	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.161C>T	p.Ala54Val	missense	Exon 3 of 28	ENSP00000381657.3	Q8TEK3-2
	DOT1L	ENST00000686010.1		c.161C>T	p.Ala54Val	missense	Exon 3 of 28	ENSP00000510335.1	A0A8I5QL06
	DOT1L	ENST00000936177.1		c.161C>T	p.Ala54Val	missense	Exon 3 of 28	ENSP00000606236.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.011	D
Sift4G	Benign	0.34	T
Vest4		0.71
MutPred		0.45		Gain of catalytic residue at M55 (P = 0.0456)
MVP		0.69
MPC		2.7
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.55
gMVP		0.98
Mutation Taster		=42/58	disease causing

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

hg19: chr19-2185889; COSMIC: COSV67110359;