19-2193760-G-A

Position:

• chr19-2193760-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032482.3(DOT1L):​c.565G>A​(p.Asp189Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.25

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOT1L	NM_032482.3	c.565G>A	p.Asp189Asn	missense_variant	6/28	ENST00000398665.8	NP_115871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOT1L	ENST00000398665.8	c.565G>A	p.Asp189Asn	missense_variant	6/28	1	NM_032482.3	ENSP00000381657.3
DOT1L	ENST00000686010.1	c.565G>A	p.Asp189Asn	missense_variant	6/28			ENSP00000510335.1
DOT1L	ENST00000452696.5	c.493G>A	p.Asp165Asn	missense_variant	6/8	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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 28, 2024

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	0.58
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.013	D;T
Sift4G	Uncertain	0.031	D;T
Vest4		0.64
MutPred		0.58		Gain of catalytic residue at D189 (P = 0.0028);.;
MVP		0.82
MPC		2.8
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.68
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr19-2193759;