rs1553414070

Positions:

• chr2-25247704-G-A
• chr2-25247704-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BS2_Supporting

The NM_022552.5(DNMT3A):​c.901C>T​(p.Arg301Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,332 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DNMT3A NM_022552.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a region_of_interest Interaction with DNMT1 and DNMT3B (size 204) in uniprot entity DNM3A_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_022552.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-25247704-G-A is Pathogenic according to our data. Variant chr2-25247704-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432039.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.901C>T	p.Arg301Trp	missense_variant	8/23	ENST00000321117.10	NP_072046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10	c.901C>T	p.Arg301Trp	missense_variant	8/23	1	NM_022552.5	ENSP00000324375	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461332 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726992

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29900417) -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 28, 2022

The c.901C>T (p.R301W) alteration is located in exon 8 (coding exon 7) of the DNMT3A gene. This alteration results from a C to T substitution at nucleotide position 901, causing the arginine (R) at amino acid position 301 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported to be de novo in an individual with postnatal overgrowth (height and head circumference greater than two standard deviations above the mean), mild intellectual disability, and joint hypermobility (Tatton-Brown, 2018). Additionally, this alteration was reported in an individual with overgrowth, developmental delay, and autism (Smith, 2021). This amino acid position is well conserved in available vertebrate species. The p.R301 amino acid is located in the PWWP domain of the DNMT3A protein, which spans 143 amino acid residues (Qiu, 2002). The PWWP domain is named after a highly conserved proline-tryptophan-tryptophan-proline motif, but in DNMT3A and DNMT3B, this motif consists of serine-tryptophan-tryptophan-proline (amino acid residues 304-307). Disruption of the PWWP domains in DNMT3A and DNMT3B prevents the association with heterochromatin and abolishes their methylation ability, suggesting that the PWWP domain plays an important role in the functional specialization of DNMT3A (Chen, 2004). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D;.;D;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Benign	1.7	L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Benign	0.069	T;T;T;T
Polyphen		0.78	P;.;P;.
Vest4		0.76
MutPred		0.57		Loss of solvent accessibility (P = 0.0217);.;Loss of solvent accessibility (P = 0.0217);.;
MVP		0.67
MPC		2.1
ClinPred		0.98	D
GERP RS		5.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.89
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1553414070; hg19: chr2-25470573; COSMIC: COSV53046262; COSMIC: COSV53046262;