rs147001633

Variant names:

• chr2-25234373-C-T
• rs147001633
• NM_022552.5:c.2645G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-25234373-C-T
• chr2-25234373-C-A
• chr2-25234373-C-G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 15P and 1B. PS3 PM5 PP3 PP5_Very_Strong BP4

The NM_022552.5(DNMT3A):​c.2645G>A​(p.Arg882His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000265 in 1,612,436 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000566073: Published functional studies of HEK293T cells expressing the R882H variant demonstrate severely reduced methyltransferase activity compared to wild-type cells due to a dramatically reduced ability to homotetramerize (Russler-Germain et al., 2014)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R882S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: DNMT3A NM_022552.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17 O:3
• Conservation: PhyloP100: 7.90
• Publications: 527 publications found

Genes affected

DNMT3A (HGNC:2978): (DNA methyltransferase 3 alpha) CpG methylation is an epigenetic modification that is important for embryonic development, imprinting, and X-chromosome inactivation. Studies in mice have demonstrated that DNA methylation is required for mammalian development. This gene encodes a DNA methyltransferase that is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes to the cytoplasm and nucleus and its expression is developmentally regulated. [provided by RefSeq, Mar 2016]

DNMT3A Gene-Disease associations (from GenCC):

• Tatton-Brown-Rahman overgrowth syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Illumina, Ambry Genetics, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• Heyn-Sproul-Jackson syndrome

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000566073: Published functional studies of HEK293T cells expressing the R882H variant demonstrate severely reduced methyltransferase activity compared to wild-type cells due to a dramatically reduced ability to homotetramerize (Russler-Germain et al., 2014); SCV000655299: Experimental studies have shown that this missense change affects DNMT3A function (PMID: 22722925, 24622842, 24656771, 26876596).; SCV004046512: Functional studies demonstrate that this variant impairs DNA methyltransferase activity resulting in hypomethylation of regions throughout the genome [PMID:31620784, 31582562, 32385248, others].; SCV006074583: PS3 (functional studies); SCV000740689: Functional studies indicate this alteration impairs DNA methyltransferase activity and results in hypomethylation at differentially-methylated regions within the genome (Russler-Germain, 2014; Emperle, 2018; Emperle, 2019; Nguyen, 2019; Norvil, 2020; Anteneh, 2020).; SCV002516987: Functional studies have demonstrated approximately 80% reduction of methyltransferase activity for this mutant (https://pubmed.ncbi.nlm.nih.gov/24656771/).; SCV004848448: "In vitro functional studies further support an impact on protein function" (Russler-Germain 2014 PMID: 24656771).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-25234374-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 375884.
• PP3: Multiple lines of computational evidence support a deleterious effect 11: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Dann, M_CAP, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 2-25234373-C-T is Pathogenic according to our data. Variant chr2-25234373-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38679647). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022552.5. 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
	DNMT3A	NM_022552.5	MANE Select	c.2645G>A	p.Arg882His	missense	Exon 23 of 23	NP_072046.2
	DNMT3A	NM_175629.2		c.2645G>A	p.Arg882His	missense	Exon 23 of 23	NP_783328.1	Q9Y6K1-1
	DNMT3A	NM_001320893.1		c.2189G>A	p.Arg730His	missense	Exon 18 of 18	NP_001307822.1	Q9Y6K1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3A	ENST00000321117.10	TSL:1 MANE Select	c.2645G>A	p.Arg882His	missense	Exon 23 of 23	ENSP00000324375.5	Q9Y6K1-1
	DNMT3A	ENST00000264709.7	TSL:1	c.2645G>A	p.Arg882His	missense	Exon 23 of 23	ENSP00000264709.3	Q9Y6K1-1
	DNMT3A	ENST00000380746.8	TSL:1	c.2078G>A	p.Arg693His	missense	Exon 19 of 19	ENSP00000370122.4	Q9Y6K1-2

Frequencies

GnomAD3 genomes AF: 0.000369 AC: 56 AN: 151936 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000508

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000219 AC: 55 AN: 251040 AF XY: 0.000214

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000544

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000254 AC: 371 AN: 1460500 Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 176 AN XY: 726560

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000389 AC: 13 AN: 33452

American (AMR) AF: 0.000157 AC: 7 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000575 AC: 15 AN: 26106

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39652

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86180

European-Finnish (FIN) AF: 0.000244 AC: 13 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000257 AC: 286 AN: 1110930

Other (OTH) AF: 0.000149 AC: 9 AN: 60352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000369 AC: 56 AN: 151936 Hom.: 0 Cov.: 32 AF XY: 0.000323 AC XY: 24 AN XY: 74240

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000508 AC: 21 AN: 41362

American (AMR) AF: 0.0000655 AC: 1 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000442 AC: 30 AN: 67940

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000803 Hom.: 0

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000593 AC: 72

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Tatton-Brown-Rahman overgrowth syndrome (6)
3	-	-	Acute myeloid leukemia (4)
2	-	-	not provided (2)
1	-	-	Abnormality of the nervous system (1)
1	-	-	Clonal Cytopenia of Undetermined Significance (1)
1	-	-	EBV-positive nodal T- and NK-cell lymphoma (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Intellectual disability (1)
1	-	-	not specified (1)
-	-	-	DNMT3A-related disorder (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.39	T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.050	T
Polyphen		0.65	P
Vest4		0.65
MVP		0.56
MPC		1.4
ClinPred		0.82	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.58
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147001633; hg19: chr2-25457242; COSMIC: COSV53036153; COSMIC: COSV53036153;