Genetic Variant DOT1L:c.81+9C>G (chr19-2164274-C-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_032482.3(DOT1L):c.81+9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,261,432 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 29)

Exomes 𝑓: 0.00010 ( 1 hom. )

Consequence

DOT1L
NM_032482.3 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.67).

BP6

Variant 19-2164274-C-G is Benign according to our data. Variant chr19-2164274-C-G is described in ClinVar as Benign. ClinVar VariationId is 725649.Status of the report is criteria_provided_single_submitter, 1 stars.

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>G		intron	N/A	NP_115871.1	Q8TEK3-2
	DOT1L	NM_001411141.1		c.81+9C>G		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>G	intron	N/A	ENSP00000381657.3	Q8TEK3-2
DOT1L	ENST00000686010.1		c.81+9C>G	intron	N/A	ENSP00000510335.1	A0A8I5QL06
DOT1L	ENST00000936177.1		c.81+9C>G	intron	N/A	ENSP00000606236.1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

218

AN:

151938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00490

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00145

GnomAD2 exomes

AF:

0.000298

AC:

AN:

33588

AF XY:

0.000106

show subpopulations

Gnomad AFR exome

AF:

0.00492

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

114

AN:

1109384

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

527964

show subpopulations

African (AFR)

AF:

0.00422

AC:

AN:

23482

American (AMR)

AF:

0.000265

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:

0.00

AC:

AN:

933138

Other (OTH)

AF:

0.000270

AC:

AN:

44480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.00143

AC:

218

AN:

152048

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00489

AC:

203

AN:

41530

American (AMR)

AF:

0.000720

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10576

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67916

Other (OTH)

AF:

0.00143

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.000712

Hom.:

Bravo

AF:

0.00165

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

8.2

(source)

DANN

Benign

0.58

PhyloP100

2.5

PromoterAI

0.090

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over