Variant chr19-2189750-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_032482.3(DOT1L):c.219G>A(p.Arg73Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,611,814 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0026 ( 40 hom. )

Consequence

DOT1L
NM_032482.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.17

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP6

Variant 19-2189750-G-A is Benign according to our data. Variant chr19-2189750-G-A is described in ClinVar as [Benign]. Clinvar id is 728331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.17 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00255 (3722/1459490) while in subpopulation EAS AF= 0.0298 (1182/39698). AF 95% confidence interval is 0.0284. There are 40 homozygotes in gnomad4_exome. There are 1897 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 40 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DOT1L	NM_032482.3 linkuse as main transcript	c.219G>A	p.Arg73Arg	synonymous_variant	4/28	ENST00000398665.8	NP_115871.1	Q8TEK3-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DOT1L	ENST00000398665.8 linkuse as main transcript	c.219G>A	p.Arg73Arg	synonymous_variant	4/28	1	NM_032482.3	ENSP00000381657.3		Q8TEK3-2

Frequencies

GnomAD3 genomes

AF:

0.00225

AC:

342

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.0127

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00461

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00300

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00289

AC:

714

AN:

247398

Hom.:

AF XY:

0.00281

AC XY:

378

AN XY:

134520

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00209

Gnomad EAS exome

AF:

0.0150

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00362

Gnomad NFE exome

AF:

0.00290

Gnomad OTH exome

AF:

0.00315

GnomAD4 exome

AF:

0.00255

AC:

3722

AN:

1459490

Hom.:

Cov.:

AF XY:

0.00261

AC XY:

1897

AN XY:

726252

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00302

Gnomad4 EAS exome

AF:

0.0298

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00391

Gnomad4 NFE exome

AF:

0.00192

Gnomad4 OTH exome

AF:

0.00177

GnomAD4 genome

AF:

0.00225

AC:

342

AN:

152324

Hom.:

Cov.:

AF XY:

0.00218

AC XY:

162

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.0129

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00461

Gnomad4 NFE

AF:

0.00300

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00343

Hom.:

Bravo

AF:

0.00180

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00261

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Benign

0.62

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over