21-44258534-C-T

Variant names:

• chr21-44258534-C-T
• rs756247540
• NM_175867.3:c.505G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_175867.3(DNMT3L):​c.505G>A​(p.Asp169Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,574,422 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (1 hom.)
• Consequence: DNMT3L NM_175867.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08219537).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3L	NM_175867.3	c.505G>A	p.Asp169Asn	missense_variant	Exon 6 of 12	ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4	c.505G>A	p.Asp169Asn	missense_variant	Exon 6 of 12		NP_037501.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3	c.505G>A	p.Asp169Asn	missense_variant	Exon 6 of 12	1	NM_175867.3	ENSP00000486001.1
DNMT3L	ENST00000270172.7	c.505G>A	p.Asp169Asn	missense_variant	Exon 6 of 12	1		ENSP00000270172.3
DNMT3L	ENST00000431166.1	c.460G>A	p.Asp154Asn	missense_variant	Exon 5 of 9	5		ENSP00000400242.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152264 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000688 AC: 13 AN: 188936 Hom.: 1 AF XY: 0.0000391 AC XY: 4 AN XY: 102390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000117

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000126

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000162 AC: 23 AN: 1422158 Hom.: 1 Cov.: 31 AF XY: 0.00000994 AC XY: 7 AN XY: 704234

Gnomad4 AFR exome AF: 0.0000613

Gnomad4 AMR exome AF: 0.000258

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000532

Gnomad4 SAS exome AF: 0.0000488

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000366

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74386

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000334 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.505G>A (p.D169N) alteration is located in exon 6 (coding exon 5) of the DNMT3L gene. This alteration results from a G to A substitution at nucleotide position 505, causing the aspartic acid (D) at amino acid position 169 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.16	.;T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.082	T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N;.;N
REVEL	Benign	0.23
Sift	Benign	0.14	T;.;T
Sift4G	Benign	0.092	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.43
MutPred		0.22		Gain of MoRF binding (P = 0.0632);Gain of MoRF binding (P = 0.0632);.;
MVP		0.86
MPC		0.28
ClinPred		0.13	T
GERP RS		3.7
Varity_R		0.18
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs756247540; hg19: chr21-45678417;