2-25234373-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. 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 (★★). 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: 505 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: Illumina, Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Heyn-Sproul-Jackson syndrome

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 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: 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

Selected	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
	DNMT3A	NM_001320893.1		c.2189G>A	p.Arg730His	missense	Exon 18 of 18	NP_001307822.1

Ensembl Transcripts

Selected	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
	DNMT3A	ENST00000264709.7	TSL:1	c.2645G>A	p.Arg882His	missense	Exon 23 of 23	ENSP00000264709.3
	DNMT3A	ENST00000380746.8	TSL:1	c.2078G>A	p.Arg693His	missense	Exon 19 of 19	ENSP00000370122.4

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 as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

View on ClinVar

Computational scores

Other links and lift over

dbSNP: rs147001633; hg19: chr2-25457242; COSMIC: COSV53036153; COSMIC: COSV53036153;