NM_006892.4:c.-274C>T

Variant names:

• chr20-32762432-C-T
• rs139762513
• NM_006892.4:c.-274C>T

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.-274C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0209 in 157,506 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (46 hom., cov: 32)
  • Exomes 𝑓: 0.031 (5 hom.)
• Consequence: DNMT3B NM_006892.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.28
• Publications: 1 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), ClinGen, Ambry Genetics, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 20-32762432-C-T is Benign according to our data. Variant chr20-32762432-C-T is described in ClinVar as Benign. ClinVar VariationId is 338146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0206 (3118/151724) while in subpopulation NFE AF = 0.0303 (2057/67832). AF 95% confidence interval is 0.0292. There are 46 homozygotes in GnomAd4. There are 1462 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 46 AD,AR 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.-274C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_006892.4	MANE Select	c.-274C>T		5_prime_UTR	Exon 1 of 23	NP_008823.1	Q9UBC3-1
	DNMT3B	NM_175848.2		c.-274C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 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.-274C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 23	ENSP00000328547.2	Q9UBC3-1
	DNMT3B	ENST00000348286.6	TSL:1	c.-274C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 20	ENSP00000337764.2	Q9UBC3-3
	DNMT3B	ENST00000328111.6	TSL:1 MANE Select	c.-274C>T		5_prime_UTR	Exon 1 of 23	ENSP00000328547.2	Q9UBC3-1

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3118 AN: 151616 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00445

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0171

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0233

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0303

Gnomad OTH AF: 0.0236

GnomAD2 exomes AF: 0.0124 AC: 4 AN: 322 AF XY: 0.0106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0311 AC: 180 AN: 5782 Hom.: 5 Cov.: 0 AF XY: 0.0284 AC XY: 113 AN XY: 3984

African (AFR) AF: 0.00 AC: 0 AN: 48

American (AMR) AF: 0.00 AC: 0 AN: 38

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 6 AN: 48

East Asian (EAS) AF: 0.00 AC: 0 AN: 170

South Asian (SAS) AF: 0.0188 AC: 11 AN: 584

European-Finnish (FIN) AF: 0.0978 AC: 9 AN: 92

Middle Eastern (MID) AF: 0.0227 AC: 1 AN: 44

European-Non Finnish (NFE) AF: 0.0321 AC: 146 AN: 4550

Other (OTH) AF: 0.0337 AC: 7 AN: 208

GnomAD4 genome AF: 0.0206 AC: 3118 AN: 151724 Hom.: 46 Cov.: 32 AF XY: 0.0197 AC XY: 1462 AN XY: 74178

African (AFR) AF: 0.00443 AC: 184 AN: 41504

American (AMR) AF: 0.0170 AC: 260 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0539 AC: 187 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.00828 AC: 40 AN: 4830

European-Finnish (FIN) AF: 0.0233 AC: 242 AN: 10404

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0303 AC: 2057 AN: 67832

Other (OTH) AF: 0.0233 AC: 49 AN: 2102

Alfa AF: 0.0257 Hom.: 6

Bravo AF: 0.0198

Asia WGS AF: 0.00690 AC: 24 AN: 3346

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency-centromeric instability-facial anomalies syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	11
DANN	Benign	0.87
PhyloP100		-1.3
PromoterAI		-0.027	Neutral
Mutation Taster		=300/0	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: rs139762513; hg19: chr20-31350238;