21-44250870-C-T

Variant names:

• chr21-44250870-C-T
• rs750537121
• NM_175867.3:c.849G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_175867.3(DNMT3L):​c.849G>A​(p.Met283Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: DNMT3L NM_175867.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0660

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]

DNMT3L-AS1 (HGNC:40189): (DNMT3L antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1571149).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3L	NM_175867.3	c.849G>A	p.Met283Ile	missense_variant	Exon 10 of 12	ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4	c.849G>A	p.Met283Ile	missense_variant	Exon 10 of 12		NP_037501.2
DNMT3L-AS1	NR_135514.1	n.58C>T		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3	c.849G>A	p.Met283Ile	missense_variant	Exon 10 of 12	1	NM_175867.3	ENSP00000486001.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 250512 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135600

Gnomad AFR exome AF: 0.000371

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.000122 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.849G>A (p.M283I) alteration is located in exon 10 (coding exon 9) of the DNMT3L gene. This alteration results from a G to A substitution at nucleotide position 849, causing the methionine (M) at amino acid position 283 to be replaced by an isoleucine (I). 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	Uncertain	0.55
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.27	.;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M;M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.2	N;.;N
REVEL	Benign	0.050
Sift	Benign	0.16	T;.;T
Sift4G	Benign	0.16	T;T;T
Polyphen		0.066	B;B;.
Vest4		0.23
MutPred		0.28		Gain of catalytic residue at L288 (P = 0.0691);Gain of catalytic residue at L288 (P = 0.0691);.;
MVP		0.28
MPC		0.20
ClinPred		0.044	T
GERP RS		1.9
Varity_R		0.20
gMVP		0.41

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: rs750537121; hg19: chr21-45670753; COSMIC: COSV99533169;