NM_022552.5:c.178-4696G>A

Variant names:

• chr2-25287407-C-T
• rs11677670
• NM_022552.5:c.178-4696G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022552.5(DNMT3A):​c.178-4696G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 152,112 control chromosomes in the GnomAD database, including 1,592 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.12 (1592 hom., cov: 32)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

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.178-4696G>A		intron	N/A	NP_072046.2
	DNMT3A	NM_175629.2		c.178-4696G>A		intron	N/A	NP_783328.1	Q9Y6K1-1
	DNMT3A	NM_001320892.2		c.178-4696G>A		intron	N/A	NP_001307821.1	Q9Y6K1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3A	ENST00000321117.10	TSL:1 MANE Select	c.178-4696G>A		intron	N/A	ENSP00000324375.5	Q9Y6K1-1
	DNMT3A	ENST00000264709.7	TSL:1	c.178-4696G>A		intron	N/A	ENSP00000264709.3	Q9Y6K1-1
	DNMT3A	ENST00000406659.3	TSL:1	c.178-4696G>A		intron	N/A	ENSP00000384852.3	Q9Y6K1-3

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18799 AN: 151994 Hom.: 1592 Cov.: 32

Gnomad AFR AF: 0.0321

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.0960

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.124

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.186

Gnomad OTH AF: 0.138

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.124 AC: 18798 AN: 152112 Hom.: 1592 Cov.: 32 AF XY: 0.119 AC XY: 8847 AN XY: 74360

African (AFR) AF: 0.0321 AC: 1330 AN: 41496

American (AMR) AF: 0.0958 AC: 1463 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 781 AN: 3470

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5186

South Asian (SAS) AF: 0.147 AC: 710 AN: 4816

European-Finnish (FIN) AF: 0.124 AC: 1309 AN: 10580

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.186 AC: 12677 AN: 67980

Other (OTH) AF: 0.135 AC: 285 AN: 2106

Alfa AF: 0.176 Hom.: 3551

Bravo AF: 0.117

Asia WGS AF: 0.0620 AC: 214 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.42
DANN	Benign	0.60
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11677670; hg19: chr2-25510276;