chr21-44261696-C-T

Position:

• chr21-44261696-C-T

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -8 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT3L	NM_175867.3	c.-8+44G>A		intron_variant		ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4	c.-8+44G>A		intron_variant			NP_037501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3	c.-8+44G>A		intron_variant		1	NM_175867.3	ENSP00000486001.1
DNMT3L	ENST00000270172.7	c.-8+44G>A		intron_variant		1		ENSP00000270172.3
DNMT3L	ENST00000431166.1	c.-8+44G>A		intron_variant		5		ENSP00000400242.1

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

Gnomad4 AFR exome AF: 0.140

Gnomad4 AMR exome AF: 0.0492

Gnomad4 ASJ exome AF: 0.0745

Gnomad4 EAS exome AF: 0.0290

Gnomad4 SAS exome AF: 0.111

Gnomad4 FIN exome AF: 0.0588

Gnomad4 NFE exome AF: 0.0725

Gnomad4 OTH exome AF: 0.0737

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

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.0743

Gnomad4 ASJ AF: 0.0953

Gnomad4 EAS AF: 0.00465

Gnomad4 SAS AF: 0.137

Gnomad4 FIN AF: 0.0837

Gnomad4 NFE AF: 0.0881

Gnomad4 OTH AF: 0.0931

Alfa AF: 0.0882 Hom.: 613

Bravo AF: 0.108

Asia WGS AF: 0.0810 AC: 284 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	9.4
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs2838535; hg19: chr21-45681579;