NM_022552.5:c.-178+3688A>T

Variant names:

• chr2-25338138-T-A
• rs1465764
• NM_022552.5:c.-178+3688A>T

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+3688A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 152,222 control chromosomes in the GnomAD database, including 63,739 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 0.91 (63739 hom., cov: 31)
• Consequence: DNMT3A NM_022552.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.404
• Publications: 8 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3A	NM_022552.5	c.-178+3688A>T		intron_variant	Intron 1 of 22	ENST00000321117.10	NP_072046.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3A	ENST00000321117.10	c.-178+3688A>T		intron_variant	Intron 1 of 22	1	NM_022552.5	ENSP00000324375.5
DNMT3A	ENST00000264709.7	c.-178+4292A>T		intron_variant	Intron 1 of 22	1		ENSP00000264709.3
DNMT3A	ENST00000406659.3	c.-178+4292A>T		intron_variant	Intron 1 of 3	1		ENSP00000384852.3
DNMT3A	ENST00000380756.7	n.-178+4292A>T		intron_variant	Intron 1 of 23	1		ENSP00000370132.3

Frequencies

GnomAD3 genomes AF: 0.913 AC: 138811 AN: 152104 Hom.: 63693 Cov.: 31

Gnomad AFR AF: 0.951

Gnomad AMI AF: 0.956

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.881

Gnomad EAS AF: 0.772

Gnomad SAS AF: 0.925

Gnomad FIN AF: 0.967

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.929

Gnomad OTH AF: 0.891

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

GnomAD4 genome AF: 0.913 AC: 138914 AN: 152222 Hom.: 63739 Cov.: 31 AF XY: 0.910 AC XY: 67751 AN XY: 74422

African (AFR) AF: 0.951 AC: 39483 AN: 41528

American (AMR) AF: 0.748 AC: 11443 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.881 AC: 3058 AN: 3472

East Asian (EAS) AF: 0.772 AC: 3975 AN: 5150

South Asian (SAS) AF: 0.925 AC: 4463 AN: 4826

European-Finnish (FIN) AF: 0.967 AC: 10261 AN: 10608

Middle Eastern (MID) AF: 0.915 AC: 269 AN: 294

European-Non Finnish (NFE) AF: 0.929 AC: 63211 AN: 68028

Other (OTH) AF: 0.889 AC: 1879 AN: 2114

Alfa AF: 0.919 Hom.: 8013

Bravo AF: 0.897

Asia WGS AF: 0.821 AC: 2855 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.9
DANN	Benign	0.58
PhyloP100		0.40
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: rs1465764; hg19: chr2-25561007;