NM_032482.3:c.465C>G

Variant names:

• chr19-2191212-C-G
• rs11879054
• NM_032482.3:c.465C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032482.3(DOT1L):​c.465C>G​(p.Asp155Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D155D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: DOT1L NM_032482.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.937
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.027468532).

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.465C>G	p.Asp155Glu	missense	Exon 5 of 28	NP_115871.1	Q8TEK3-2
	DOT1L	NM_001411141.1		c.465C>G	p.Asp155Glu	missense	Exon 5 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.465C>G	p.Asp155Glu	missense	Exon 5 of 28	ENSP00000381657.3	Q8TEK3-2
	DOT1L	ENST00000686010.1		c.465C>G	p.Asp155Glu	missense	Exon 5 of 28	ENSP00000510335.1	A0A8I5QL06
	DOT1L	ENST00000936177.1		c.465C>G	p.Asp155Glu	missense	Exon 5 of 28	ENSP00000606236.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.8
DANN	Benign	0.40
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.3	N
PhyloP100		0.94
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.12
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.15
MutPred		0.28		Loss of ubiquitination at K152 (P = 0.0683)
MVP		0.28
MPC		1.5
ClinPred		0.058	T
GERP RS		0.16
Varity_R		0.13
gMVP		0.73
Mutation Taster		=86/14	polymorphism

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

dbSNP: rs11879054; hg19: chr19-2191211;