Genetic Variant DOT1L:c.81+9C>T (chr19-2164274-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_032482.3(DOT1L):c.81+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000901 in 1,109,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 9.0e-7 ( 0 hom. )

Consequence

DOT1L
NM_032482.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.47

Publications

0 publications found

Variant links:

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]

DOT1L links:

AP3D1 (HGNC:568): (adaptor related protein complex 3 subunit delta 1) The protein encoded by this gene is a subunit of the AP3 adaptor-like complex, which is not clathrin-associated, but is associated with the golgi region, as well as more peripheral structures. The AP-3 complex facilitates the budding of vesicles from the golgi membrane, and may be directly involved in trafficking to lysosomes. This subunit is implicated in intracellular biogenesis and trafficking of pigment granules, and possibly platelet dense granules and neurotransmitter vesicles. Defects in this gene are a cause of a new type of Hermansky-Pudlak syndrome. [provided by RefSeq, Feb 2017]

AP3D1 Gene-Disease associations (from GenCC):

Hermansky-Pudlak syndrome 10
Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

AP3D1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 (BayesDel_noAF=-0.63).

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.81+9C>T		intron	N/A	NP_115871.1	Q8TEK3-2
	DOT1L	NM_001411141.1		c.81+9C>T		intron	N/A	NP_001398070.1	A0A8I5QL06

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DOT1L	ENST00000398665.8	TSL:1 MANE Select	c.81+9C>T	intron	N/A	ENSP00000381657.3	Q8TEK3-2
DOT1L	ENST00000686010.1		c.81+9C>T	intron	N/A	ENSP00000510335.1	A0A8I5QL06
DOT1L	ENST00000936177.1		c.81+9C>T	intron	N/A	ENSP00000606236.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.01e-7

AC:

AN:

1109384

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

527964

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23482

American (AMR)

AF:

0.00

AC:

AN:

11340

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14526

East Asian (EAS)

AF:

0.00

AC:

AN:

27340

South Asian (SAS)

AF:

0.00

AC:

AN:

22358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3792

European-Non Finnish (NFE)

AF:

0.00000107

AC:

AN:

933138

Other (OTH)

AF:

0.00

AC:

AN:

44480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

8.9

(source)

DANN

Benign

0.86

PhyloP100

2.5

PromoterAI

0.027

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over