rs150682895

Variant names:

• chr20-32795432-G-A
• rs150682895
• NM_006892.4:c.1150G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006892.4(DNMT3B):​c.1150G>A​(p.Ala384Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,614,144 control chromosomes in the GnomAD database, including 115 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0095 (6 hom., cov: 32)
  • Exomes 𝑓: 0.011 (109 hom.)
• Consequence: DNMT3B NM_006892.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.217
• Publications: 12 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: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023308396).
• BP6: Variant 20-32795432-G-A is Benign according to our data. Variant chr20-32795432-G-A is described in ClinVar as Benign. ClinVar VariationId is 461480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00952 (1449/152278) while in subpopulation AMR AF = 0.0169 (259/15294). AF 95% confidence interval is 0.0152. There are 6 homozygotes in GnomAd4. There are 809 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.1150G>A	p.Ala384Thr	missense	Exon 11 of 23	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_175850.3		c.1126G>A	p.Ala376Thr	missense	Exon 10 of 22	NP_787046.1	Q9UBC3-6
	DNMT3B	NM_175848.2		c.1090G>A	p.Ala364Thr	missense	Exon 10 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.1150G>A	p.Ala384Thr	missense	Exon 11 of 23	ENSP00000328547.2	Q9UBC3-1
	DNMT3B	ENST00000201963.3	TSL:1	c.1126G>A	p.Ala376Thr	missense	Exon 10 of 22	ENSP00000201963.3	Q9UBC3-6
	DNMT3B	ENST00000348286.6	TSL:1	c.1090G>A	p.Ala364Thr	missense	Exon 10 of 20	ENSP00000337764.2	Q9UBC3-3

Frequencies

GnomAD3 genomes AF: 0.00953 AC: 1450 AN: 152160 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0155

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00903 AC: 2271 AN: 251404 AF XY: 0.00926

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00934

Gnomad ASJ exome AF: 0.00982

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.0119

Gnomad OTH exome AF: 0.0124

GnomAD4 exome AF: 0.0106 AC: 15503 AN: 1461866 Hom.: 109 Cov.: 30 AF XY: 0.0105 AC XY: 7665 AN XY: 727234

African (AFR) AF: 0.00179 AC: 60 AN: 33478

American (AMR) AF: 0.00930 AC: 416 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00869 AC: 227 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00351 AC: 303 AN: 86258

European-Finnish (FIN) AF: 0.0113 AC: 601 AN: 53420

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5768

European-Non Finnish (NFE) AF: 0.0119 AC: 13192 AN: 1112000

Other (OTH) AF: 0.0102 AC: 613 AN: 60388

GnomAD4 genome AF: 0.00952 AC: 1449 AN: 152278 Hom.: 6 Cov.: 32 AF XY: 0.0109 AC XY: 809 AN XY: 74472

African (AFR) AF: 0.00180 AC: 75 AN: 41554

American (AMR) AF: 0.0169 AC: 259 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4816

European-Finnish (FIN) AF: 0.0155 AC: 164 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0126 AC: 857 AN: 68022

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.0106 Hom.: 30

Bravo AF: 0.00896

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0115 AC: 99

ExAC AF: 0.00792 AC: 962

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0133

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (3)
-	-	1	Centromeric instability of chromosomes 1,9 and 16 and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	11
DANN	Benign	0.84
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.46	N
PhyloP100		0.22
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.86	N
REVEL	Benign	0.16
Sift	Benign	0.88	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.28
MPC		0.17
ClinPred		0.0054	T
GERP RS		2.7
Varity_R		0.026
gMVP		0.20
Mutation Taster		=98/2	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

Other links and lift over

dbSNP: rs150682895; hg19: chr20-31383238;