chr2-25234374-G-A

Variant names:

• chr2-25234374-G-A
• rs377577594
• NM_022552.5:c.2644C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5 PP3 PP5_Very_Strong

The NM_022552.5(DNMT3A):​c.2644C>T​(p.Arg882Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,613,128 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 pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). 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 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: DNMT3A NM_022552.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 10.0
• Publications: 269 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 11 ACMG points.

• 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: MetaRNN computational evidence supports a deleterious effect, 0.838
• PP5: Variant 2-25234374-G-A is Pathogenic according to our data. Variant chr2-25234374-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 375882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2644C>T	p.Arg882Cys	missense	Exon 23 of 23	NP_072046.2
	DNMT3A	NM_175629.2		c.2644C>T	p.Arg882Cys	missense	Exon 23 of 23	NP_783328.1	Q9Y6K1-1
	DNMT3A	NM_001320893.1		c.2188C>T	p.Arg730Cys	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.2644C>T	p.Arg882Cys	missense	Exon 23 of 23	ENSP00000324375.5	Q9Y6K1-1
	DNMT3A	ENST00000264709.7	TSL:1	c.2644C>T	p.Arg882Cys	missense	Exon 23 of 23	ENSP00000264709.3	Q9Y6K1-1
	DNMT3A	ENST00000380746.8	TSL:1	c.2077C>T	p.Arg693Cys	missense	Exon 19 of 19	ENSP00000370122.4	Q9Y6K1-2

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000123 AC: 31 AN: 251136 AF XY: 0.000110

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000149 AC: 218 AN: 1461066 Hom.: 0 Cov.: 31 AF XY: 0.000149 AC XY: 108 AN XY: 726872

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

African (AFR) AF: 0.000120 AC: 4 AN: 33466

American (AMR) AF: 0.0000447 AC: 2 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26116

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39682

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86184

European-Finnish (FIN) AF: 0.000112 AC: 6 AN: 53390

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.000161 AC: 179 AN: 1111386

Other (OTH) AF: 0.0000994 AC: 6 AN: 60374

⚠️ 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: 0.000158 AC: 24 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74282

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

African (AFR) AF: 0.000145 AC: 6 AN: 41414

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67966

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

⚠️ 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: 0.000133 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000362 AC: 44

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Tatton-Brown-Rahman overgrowth syndrome (7)
2	-	-	Acute myeloid leukemia (2)
2	-	-	not provided (2)
1	-	-	DNMT3A-related disorder (1)
1	-	-	EBV-positive nodal T- and NK-cell lymphoma (1)
1	-	-	Heyn-Sproul-Jackson syndrome (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental disorder (1)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		10
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MVP		0.83
MPC		1.5
ClinPred		0.38	T
GERP RS		5.7
Varity_R		0.94
gMVP		0.69
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs377577594; hg19: chr2-25457243; COSMIC: COSV53036332; COSMIC: COSV53036332;