chr21-44261696-C-T

Variant names:

• chr21-44261696-C-T
• rs2838535
• NM_175867.3:c.-8+44G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_175867.3(DNMT3L):​c.-8+44G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 167,914 control chromosomes in the GnomAD database, including 1,139 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 0.11 (1084 hom., cov: 31)
  • Exomes 𝑓: 0.073 (55 hom.)
• Consequence: DNMT3L NM_175867.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.72
• Publications: 4 publications found

Genes affected

DNMT3L (HGNC:2980): (DNA methyltransferase 3 like) 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 nuclear protein with similarity to DNA methyltransferases, but is not thought to function as a DNA methyltransferase as it does not contain the amino acid residues necessary for methyltransferase activity. However, it does stimulate de novo methylation by DNA cytosine methyltransferase 3 alpha and is thought to be required for the establishment of maternal genomic imprints. This protein also mediates transcriptional repression through interaction with histone deacetylase 1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175867.3. 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
	DNMT3L	NM_175867.3	MANE Select	c.-8+44G>A		intron	N/A	NP_787063.1	Q9UJW3-1
	DNMT3L	NM_013369.4		c.-8+44G>A		intron	N/A	NP_037501.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3L	ENST00000628202.3	TSL:1 MANE Select	c.-8+44G>A		intron	N/A	ENSP00000486001.1	Q9UJW3-1
	DNMT3L	ENST00000270172.7	TSL:1	c.-8+44G>A		intron	N/A	ENSP00000270172.3	Q9UJW3-2
	DNMT3L	ENST00000431166.1	TSL:5	c.-8+44G>A		intron	N/A	ENSP00000400242.1	C9J0T5

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16279 AN: 152078 Hom.: 1084 Cov.: 31

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.0744

Gnomad ASJ AF: 0.0953

Gnomad EAS AF: 0.00464

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0837

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.0880

Gnomad OTH AF: 0.0941

GnomAD4 exome AF: 0.0728 AC: 1145 AN: 15718 Hom.: 55 Cov.: 0 AF XY: 0.0782 AC XY: 645 AN XY: 8244

African (AFR) AF: 0.140 AC: 41 AN: 292

American (AMR) AF: 0.0492 AC: 88 AN: 1788

Ashkenazi Jewish (ASJ) AF: 0.0745 AC: 24 AN: 322

East Asian (EAS) AF: 0.0290 AC: 18 AN: 620

South Asian (SAS) AF: 0.111 AC: 173 AN: 1558

European-Finnish (FIN) AF: 0.0588 AC: 30 AN: 510

Middle Eastern (MID) AF: 0.0652 AC: 3 AN: 46

European-Non Finnish (NFE) AF: 0.0725 AC: 707 AN: 9754

Other (OTH) AF: 0.0737 AC: 61 AN: 828

GnomAD4 genome AF: 0.107 AC: 16290 AN: 152196 Hom.: 1084 Cov.: 31 AF XY: 0.106 AC XY: 7890 AN XY: 74428

African (AFR) AF: 0.166 AC: 6897 AN: 41514

American (AMR) AF: 0.0743 AC: 1136 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0953 AC: 331 AN: 3472

East Asian (EAS) AF: 0.00465 AC: 24 AN: 5160

South Asian (SAS) AF: 0.137 AC: 663 AN: 4826

European-Finnish (FIN) AF: 0.0837 AC: 889 AN: 10616

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0881 AC: 5988 AN: 67990

Other (OTH) AF: 0.0931 AC: 197 AN: 2116

Alfa AF: 0.0911 Hom.: 870

Bravo AF: 0.108

Asia WGS AF: 0.0810 AC: 284 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	9.4
DANN	Benign	0.66
PhyloP100		-2.7
PromoterAI		0.057	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 3

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

Other links and lift over

dbSNP: rs2838535; hg19: chr21-45681579;