rs140951214

chr19-10140812-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001130823.3(DNMT1):c.3492C>T(p.Cys1164=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000966 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: DNMT1 NM_001130823.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.316

Genes affected

DNMT1 (HGNC:2976): (DNA methyltransferase 1) This gene encodes an enzyme that transfers methyl groups to cytosine nucleotides of genomic DNA. This protein is the major enzyme responsible for maintaining methylation patterns following DNA replication and shows a preference for hemi-methylated DNA. Methylation of DNA is an important component of mammalian epigenetic gene regulation. Aberrant methylation patterns are found in human tumors and associated with developmental abnormalities. Variation in this gene has been associated with cerebellar ataxia, deafness, and narcolepsy, and neuropathy, hereditary sensory, type IE. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 19-10140812-G-A is Benign according to our data. Variant chr19-10140812-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 472271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.316 with no splicing effect.
• BS2: High AC in GnomAd at 74 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.3492C>T	p.Cys1164=	synonymous_variant	32/41	ENST00000359526.9
DNMT1	NM_001318730.2	c.3444C>T	p.Cys1148=	synonymous_variant	31/40
DNMT1	NM_001379.4	c.3444C>T	p.Cys1148=	synonymous_variant	31/40
DNMT1	NM_001318731.2	c.3129C>T	p.Cys1043=	synonymous_variant	32/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.3492C>T	p.Cys1164=	synonymous_variant	32/41	1	NM_001130823.3

Frequencies

GnomAD3 genomes AF: 0.000486 AC: 74 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000159 AC: 40 AN: 251258 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135812

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461796 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30 AN XY: 727188

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74450

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000597

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 18, 2020	- -

DNMT1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	1.3
Dann	Benign	0.55
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs140951214; hg19: chr19-10251488;