19-2193767-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOT1L	NM_032482.3	c.572C>T	p.Pro191Leu	missense_variant	Exon 6 of 28	ENST00000398665.8	NP_115871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOT1L	ENST00000398665.8	c.572C>T	p.Pro191Leu	missense_variant	Exon 6 of 28	1	NM_032482.3	ENSP00000381657.3
DOT1L	ENST00000686010.1	c.572C>T	p.Pro191Leu	missense_variant	Exon 6 of 28			ENSP00000510335.1
DOT1L	ENST00000452696.5	c.500C>T	p.Pro167Leu	missense_variant	Exon 6 of 8	3		ENSP00000404284.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 28, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-9.6	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.020	D;D
Sift4G	Pathogenic	0.0	D;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-2193766;