rs150316325

Variant names:

• chr19-2189750-G-A
• rs150316325
• NM_032482.3:c.219G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-2189750-G-A
• chr19-2189750-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.17
• Publications: 5 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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. GnomAdExome4 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 GnomAdExome4. There are 1897 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 40 gene

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.219G>A	p.Arg73Arg	synonymous	Exon 4 of 28	NP_115871.1	Q8TEK3-2
	DOT1L	NM_001411141.1		c.219G>A	p.Arg73Arg	synonymous	Exon 4 of 28	NP_001398070.1	A0A8I5QL06

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOT1L	ENST00000398665.8	TSL:1 MANE Select	c.219G>A	p.Arg73Arg	synonymous	Exon 4 of 28	ENSP00000381657.3	Q8TEK3-2
	DOT1L	ENST00000686010.1		c.219G>A	p.Arg73Arg	synonymous	Exon 4 of 28	ENSP00000510335.1	A0A8I5QL06
	DOT1L	ENST00000936177.1		c.219G>A	p.Arg73Arg	synonymous	Exon 4 of 28	ENSP00000606236.1

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 342 AN: 152206 Hom.: 1 Cov.: 33

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

GnomAD2 exomes AF: 0.00289 AC: 714 AN: 247398 AF XY: 0.00281

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 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

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 79 AN: 26134

East Asian (EAS) AF: 0.0298 AC: 1182 AN: 39698

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86258

European-Finnish (FIN) AF: 0.00391 AC: 200 AN: 51092

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00192 AC: 2130 AN: 1111968

Other (OTH) AF: 0.00177 AC: 107 AN: 60376

GnomAD4 genome AF: 0.00225 AC: 342 AN: 152324 Hom.: 1 Cov.: 33 AF XY: 0.00218 AC XY: 162 AN XY: 74464

African (AFR) AF: 0.000192 AC: 8 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.0129 AC: 67 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00461 AC: 49 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00300 AC: 204 AN: 68024

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.62
PhyloP100		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

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