2-25245305-T-C

Variant names:

• chr2-25245305-T-C
• rs149738328
• NM_022552.5:c.1502A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6_Very_Strong BS2_Supporting

The NM_022552.5(DNMT3A):​c.1502A>G​(p.Asn501Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,613,896 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N501I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: DNMT3A NM_022552.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 7.90
• Publications: 20 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: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_022552.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.23841253).
• BP6: Variant 2-25245305-T-C is Benign according to our data. Variant chr2-25245305-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 133986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 38 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1502A>G	p.Asn501Ser	missense	Exon 13 of 23	NP_072046.2
	DNMT3A	NM_175629.2		c.1502A>G	p.Asn501Ser	missense	Exon 13 of 23	NP_783328.1	Q9Y6K1-1
	DNMT3A	NM_001320893.1		c.1046A>G	p.Asn349Ser	missense	Exon 8 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.1502A>G	p.Asn501Ser	missense	Exon 13 of 23	ENSP00000324375.5	Q9Y6K1-1
	DNMT3A	ENST00000264709.7	TSL:1	c.1502A>G	p.Asn501Ser	missense	Exon 13 of 23	ENSP00000264709.3	Q9Y6K1-1
	DNMT3A	ENST00000380746.8	TSL:1	c.935A>G	p.Asn312Ser	missense	Exon 9 of 19	ENSP00000370122.4	Q9Y6K1-2

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000320 AC: 80 AN: 250126 AF XY: 0.000385

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000434

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000340 AC: 497 AN: 1461646 Hom.: 1 Cov.: 31 AF XY: 0.000345 AC XY: 251 AN XY: 727094

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.000335 AC: 15 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86154

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000385 AC: 428 AN: 1111950

Other (OTH) AF: 0.000232 AC: 14 AN: 60380

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74424

African (AFR) AF: 0.0000722 AC: 3 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000495 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000296 AC: 36

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	DNMT3A-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Tatton-Brown-Rahman overgrowth syndrome (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.43
Sift	Benign	0.076	T
Sift4G	Benign	0.21	T
Polyphen		0.44	B
Vest4		0.65
MVP		0.52
MPC		0.78
ClinPred		0.092	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.50
Mutation Taster		=96/4	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: rs149738328; hg19: chr2-25468174; COSMIC: COSV53038482;