chr19-2193767-C-T

Variant names:

• chr19-2193767-C-T
• rs2144753125
• NM_032482.3:c.572C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_032482.3(DOT1L):​c.572C>T​(p.Pro191Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOT1L NM_032482.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.53
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

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.572C>T	p.Pro191Leu	missense	Exon 6 of 28	NP_115871.1	Q8TEK3-2
	DOT1L	NM_001411141.1		c.572C>T	p.Pro191Leu	missense	Exon 6 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.572C>T	p.Pro191Leu	missense	Exon 6 of 28	ENSP00000381657.3	Q8TEK3-2
	DOT1L	ENST00000686010.1		c.572C>T	p.Pro191Leu	missense	Exon 6 of 28	ENSP00000510335.1	A0A8I5QL06
	DOT1L	ENST00000936177.1		c.572C>T	p.Pro191Leu	missense	Exon 6 of 28	ENSP00000606236.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.5
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-9.6	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.020	D
Sift4G	Pathogenic	0.0	D
Vest4		0.93
MutPred		0.64		Loss of disorder (P = 0.0294)
MVP		0.85
MPC		2.9
ClinPred		1.0	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.99
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2144753125; hg19: chr19-2193766;