19-2210498-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_032482.3(DOT1L):c.1104C>T(p.Ala368=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000578 in 1,594,396 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (5 hom.)
• Consequence: DOT1L NM_032482.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.16

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 19-2210498-C-T is Benign according to our data. Variant chr19-2210498-C-T is described in ClinVar as [Benign]. Clinvar id is 720086.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.16 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOT1L	NM_032482.3	c.1104C>T	p.Ala368=	synonymous_variant	13/28	ENST00000398665.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOT1L	ENST00000398665.8	c.1104C>T	p.Ala368=	synonymous_variant	13/28	1	NM_032482.3	P2
DOT1L	ENST00000686010.1	c.1104C>T	p.Ala368=	synonymous_variant	13/28			A2

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 459 AN: 152236 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

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: 0.0000441

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.000688 AC: 154 AN: 223916 Hom.: 1 AF XY: 0.000515 AC XY: 64 AN XY: 124258

Gnomad AFR exome AF: 0.00977

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000599

Gnomad SAS exome AF: 0.0000338

Gnomad FIN exome AF: 0.0000597

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000543

GnomAD4 exome AF: 0.000316 AC: 455 AN: 1442042 Hom.: 5 Cov.: 32 AF XY: 0.000251 AC XY: 180 AN XY: 716002

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.000445

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.0000585

Gnomad4 FIN exome AF: 0.0000629

Gnomad4 NFE exome AF: 0.0000145

Gnomad4 OTH exome AF: 0.000757

GnomAD4 genome AF: 0.00307 AC: 467 AN: 152354 Hom.: 1 Cov.: 33 AF XY: 0.00318 AC XY: 237 AN XY: 74502

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.000961 Hom.: 0

Bravo AF: 0.00367

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 10, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.087
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

Other links and lift over

dbSNP: rs142127010; hg19: chr19-2210497;