21-44251653-G-T

Variant names:

• chr21-44251653-G-T
• rs376786065
• NM_175867.3:c.739C>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_175867.3(DNMT3L):​c.739C>A​(p.Pro247Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/21 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: -1.18

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060958356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT3L	NM_175867.3	c.739C>A	p.Pro247Thr	missense_variant	Exon 9 of 12	ENST00000628202.3	NP_787063.1
DNMT3L	NM_013369.4	c.739C>A	p.Pro247Thr	missense_variant	Exon 9 of 12		NP_037501.2
DNMT3L-AS1	NR_135514.1	n.*132G>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT3L	ENST00000628202.3	c.739C>A	p.Pro247Thr	missense_variant	Exon 9 of 12	1	NM_175867.3	ENSP00000486001.1
DNMT3L	ENST00000270172.7	c.739C>A	p.Pro247Thr	missense_variant	Exon 9 of 12	1		ENSP00000270172.3
DNMT3L	ENST00000431166.1	c.694C>A	p.Pro232Thr	missense_variant	Exon 8 of 9	5		ENSP00000400242.1
DNMT3L-AS1	ENST00000442785.1	n.*133G>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0000440 AC: 11 AN: 249776 Hom.: 0 AF XY: 0.0000592 AC XY: 8 AN XY: 135232

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

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: 0.0000442

Gnomad OTH exome AF: 0.000165

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

Alfa AF: 0.000223 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.739C>A (p.P247T) alteration is located in exon 9 (coding exon 8) of the DNMT3L gene. This alteration results from a C to A substitution at nucleotide position 739, causing the proline (P) at amino acid position 247 to be replaced by a threonine (T). 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	0.093
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	2.2
DANN	Benign	0.74
DEOGEN2	Benign	0.23	.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.56	T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.22	N;.;N
REVEL	Benign	0.088
Sift	Benign	0.046	D;.;T
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.17
MVP		0.40
MPC		0.18
ClinPred		0.030	T
GERP RS		-1.6
Varity_R		0.082
gMVP		0.64

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: rs376786065; hg19: chr21-45671536;