19-2191046-C-T

Variant names:

• chr19-2191046-C-T
• rs781606489
• NM_032482.3:c.299C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_032482.3(DOT1L):​c.299C>T​(p.Thr100Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000618 in 1,456,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DOT1L NM_032482.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.68

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
• PP5: Variant 19-2191046-C-T is Pathogenic according to our data. Variant chr19-2191046-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3359220.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.35961503). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOT1L	NM_032482.3	c.299C>T	p.Thr100Met	missense_variant	Exon 5 of 28	ENST00000398665.8	NP_115871.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOT1L	ENST00000398665.8	c.299C>T	p.Thr100Met	missense_variant	Exon 5 of 28	1	NM_032482.3	ENSP00000381657.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1456324 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 724336

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

DOT1L-related condition Pathogenic:1

Apr 17, 2024

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

PMID: 37827158; Functional studies were performed in Drosophila and human cells to assess pathogenicity. The variant behaves as a gain-of-function allele in flies and leads to increased H3K79 methylation levels in flies and human cells. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.9	L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.12
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.024	D
Vest4		0.40
MutPred		0.26		Loss of phosphorylation at T100 (P = 0.0485);
MVP		0.55
MPC		2.9
ClinPred		0.94	D
GERP RS		4.8
Varity_R		0.43
gMVP		0.81

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

LitVar

Other links and lift over

dbSNP: rs781606489; hg19: chr19-2191045; COSMIC: COSV67107693;