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GeneBe

19-2189750-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_032482.3(DOT1L):c.219G>A(p.Arg73=) 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

2

Clinical Significance

Benign criteria provided, single submitter B:1

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
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_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=2.17 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
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
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAdExome at 7 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DOT1LNM_032482.3 linkuse as main transcriptc.219G>A p.Arg73= synonymous_variant 4/28 ENST00000398665.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DOT1LENST00000398665.8 linkuse as main transcriptc.219G>A p.Arg73= synonymous_variant 4/281 NM_032482.3 P2Q8TEK3-2
DOT1LENST00000686010.1 linkuse as main transcriptc.219G>A p.Arg73= synonymous_variant 4/28 A2
DOT1LENST00000452696.5 linkuse as main transcriptc.219G>A p.Arg73= synonymous_variant 4/83
DOT1LENST00000478937.3 linkuse as main transcriptc.*90G>A 3_prime_UTR_variant, NMD_transcript_variant 5/63

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00225
AC:
342
AN:
152206
Hom.:
1
Cov.:
33
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.:
7
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.:
40
Cov.:
31
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
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00225
AC:
342
AN:
152324
Hom.:
1
Cov.:
33
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.:
1
Bravo
AF:
0.00180
Asia WGS
AF:
0.00837
AC:
29
AN:
3478
EpiCase
AF:
0.00202
EpiControl
AF:
0.00261

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJul 20, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.48
Cadd
Benign
12
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.

Other links and lift over

dbSNP: rs150316325; hg19: chr19-2189749; COSMIC: COSV67109370; API