rs145632647

Variant names:

• chr20-32791673-G-A
• rs145632647
• NM_006892.4:c.886G>A
• DNMT3B p.Val296Ile

Your query was ambiguous. Multiple possible variants found:

• chr20-32791673-G-A
• chr20-32791673-G-C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006892.4(DNMT3B):​c.886G>A​(p.Val296Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000354 in 1,614,096 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (4 hom.)
• Consequence: DNMT3B NM_006892.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 2.42
• Publications: 7 publications found

Genes affected

DNMT3B (HGNC:2979): (DNA methyltransferase 3 beta) 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 DNA methyltransferase which is thought to function in de novo methylation, rather than maintenance methylation. The protein localizes primarily to the nucleus and its expression is developmentally regulated. Mutations in this gene cause the immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome. Eight alternatively spliced transcript variants have been described. The full length sequences of variants 4 and 5 have not been determined. [provided by RefSeq, May 2011]

DNMT3B Gene-Disease associations (from GenCC):

• immunodeficiency-centromeric instability-facial anomalies syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• facioscapulohumeral muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency-centromeric instability-facial anomalies syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008820653).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000847 (129/152298) while in subpopulation AFR AF = 0.00209 (87/41550). AF 95% confidence interval is 0.00174. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006892.4. 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
	DNMT3B	NM_006892.4	MANE Select	c.886G>A	p.Val296Ile	missense	Exon 8 of 23	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_175850.3		c.922G>A	p.Val308Ile	missense	Exon 8 of 22	NP_787046.1	Q9UBC3-6
	DNMT3B	NM_175848.2		c.886G>A	p.Val296Ile	missense	Exon 8 of 22	NP_787044.1	Q9UBC3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.886G>A	p.Val296Ile	missense	Exon 8 of 23	ENSP00000328547.2	Q9UBC3-1
	DNMT3B	ENST00000201963.3	TSL:1	c.922G>A	p.Val308Ile	missense	Exon 8 of 22	ENSP00000201963.3	Q9UBC3-6
	DNMT3B	ENST00000348286.6	TSL:1	c.886G>A	p.Val296Ile	missense	Exon 8 of 20	ENSP00000337764.2	Q9UBC3-3

Frequencies

GnomAD3 genomes AF: 0.000848 AC: 129 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000676 AC: 170 AN: 251472 AF XY: 0.000647

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00962

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.000302 AC: 442 AN: 1461798 Hom.: 4 Cov.: 31 AF XY: 0.000285 AC XY: 207 AN XY: 727194

African (AFR) AF: 0.00203 AC: 68 AN: 33472

American (AMR) AF: 0.000201 AC: 9 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00800 AC: 209 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000926 AC: 103 AN: 1111946

Other (OTH) AF: 0.000679 AC: 41 AN: 60386

GnomAD4 genome AF: 0.000847 AC: 129 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000779 AC XY: 58 AN XY: 74462

African (AFR) AF: 0.00209 AC: 87 AN: 41550

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00778 AC: 27 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68032

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000841 Hom.: 1

Bravo AF: 0.000782

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	2	-	Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (2)
-	-	1	Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency (1)
-	1	-	Immunodeficiency-centromeric instability-facial anomalies syndrome 1;C5561960:Facioscapulohumeral muscular dystrophy 4, digenic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.073
Sift	Benign	0.32	T
Sift4G	Benign	0.21	T
Varity_R		0.36
gMVP		0.35
Mutation Taster		=77/23	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs145632647;

hg19: chr20-31379479;

COSMIC: COSV52422366;