19-2185890-C-T

Variant names:

• chr19-2185890-C-T
• NM_032482.3:c.161C>T

Variant summary

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

The NM_032482.3(DOT1L):​c.161C>T​(p.Ala54Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DOT1L NM_032482.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.95

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 rank	MANE	Protein	UniProt
DOT1L	NM_032482.3	c.161C>T	p.Ala54Val	missense_variant	Exon 3 of 28	ENST00000398665.8	NP_115871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOT1L	ENST00000398665.8	c.161C>T	p.Ala54Val	missense_variant	Exon 3 of 28	1	NM_032482.3	ENSP00000381657.3
DOT1L	ENST00000686010.1	c.161C>T	p.Ala54Val	missense_variant	Exon 3 of 28			ENSP00000510335.1
DOT1L	ENST00000452696.5	c.161C>T	p.Ala54Val	missense_variant	Exon 3 of 8	3		ENSP00000404284.1
DOT1L	ENST00000478937.3	n.146C>T		non_coding_transcript_exon_variant	Exon 3 of 6	3		ENSP00000484015.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 22, 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; De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.011	D;T
Sift4G	Benign	0.34	T;T
Vest4		0.71
MutPred		0.45		Gain of catalytic residue at M55 (P = 0.0456);Gain of catalytic residue at M55 (P = 0.0456);
MVP		0.69
MPC		2.7
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.55
gMVP		0.98

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-2185889; COSMIC: COSV67110359;