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GeneBe

19-2191212-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_032482.3(DOT1L):c.465C>T(p.Asp155=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000744 in 1,613,910 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0038 ( 4 hom., cov: 31)
Exomes 𝑓: 0.00043 ( 5 hom. )

Consequence

DOT1L
NM_032482.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.937
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 -9 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=-0.36).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-2191212-C-T is Benign according to our data. Variant chr19-2191212-C-T is described in ClinVar as [Benign]. Clinvar id is 777359.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=0.937 with no splicing effect.
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 GnomAd at 4 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DOT1LNM_032482.3 linkuse as main transcriptc.465C>T p.Asp155= synonymous_variant 5/28 ENST00000398665.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DOT1LENST00000398665.8 linkuse as main transcriptc.465C>T p.Asp155= synonymous_variant 5/281 NM_032482.3 P2Q8TEK3-2
DOT1LENST00000686010.1 linkuse as main transcriptc.465C>T p.Asp155= synonymous_variant 5/28 A2
DOT1LENST00000452696.5 linkuse as main transcriptc.393C>T p.Asp131= synonymous_variant 5/83
DOT1LENST00000478937.3 linkuse as main transcriptc.*336C>T 3_prime_UTR_variant, NMD_transcript_variant 6/63

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00377
AC:
574
AN:
152084
Hom.:
4
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0129
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00203
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:
0.0000294
Gnomad OTH
AF:
0.00287
GnomAD3 exomes
AF:
0.000895
AC:
223
AN:
249090
Hom.:
0
AF XY:
0.000651
AC XY:
88
AN XY:
135172
show subpopulations
Gnomad AFR exome
AF:
0.0131
Gnomad AMR exome
AF:
0.000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000556
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000620
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000426
AC:
623
AN:
1461708
Hom.:
5
Cov.:
32
AF XY:
0.000364
AC XY:
265
AN XY:
727152
show subpopulations
Gnomad4 AFR exome
AF:
0.0131
Gnomad4 AMR exome
AF:
0.000604
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000971
Gnomad4 OTH exome
AF:
0.000646
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00380
AC:
578
AN:
152202
Hom.:
4
Cov.:
31
AF XY:
0.00356
AC XY:
265
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.0130
Gnomad4 AMR
AF:
0.00203
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.00218
Hom.:
1
Bravo
AF:
0.00464
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000178

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 testingInvitaeDec 28, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.36
Cadd
Benign
8.0
Dann
Benign
0.67
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: rs11879054; hg19: chr19-2191211; COSMIC: COSV67108474; API