chr19-2194533-A-G

Position:

• chr19-2194533-A-G

Variant summary

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

The NM_032482.3(DOT1L):​c.607A>G​(p.Arg203Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOT1L NM_032482.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81

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.607A>G	p.Arg203Gly	missense_variant	7/28	ENST00000398665.8	NP_115871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOT1L	ENST00000398665.8	c.607A>G	p.Arg203Gly	missense_variant	7/28	1	NM_032482.3	ENSP00000381657.3
DOT1L	ENST00000686010.1	c.607A>G	p.Arg203Gly	missense_variant	7/28			ENSP00000510335.1
DOT1L	ENST00000452696.5	c.535A>G	p.Arg179Gly	missense_variant	7/8	3		ENSP00000404284.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2024

The c.607A>G (p.R203G) alteration is located in exon 7 (coding exon 7) of the DOT1L gene. This alteration results from a A to G substitution at nucleotide position 607, causing the arginine (R) at amino acid position 203 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.0040	D;T
Vest4		0.72
MutPred		0.59		Loss of MoRF binding (P = 0.0482);.;
MVP		0.65
MPC		3.3
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.86
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-2194532;