chr19-10180405-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001130823.3(DNMT1):c.390A>G(p.Lys130Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,613,820 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 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

DNMT1
NM_001130823.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.17

Publications

2 publications found

Variant links:

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]

DNMT1 Gene-Disease associations (from GenCC):

autosomal dominant cerebellar ataxia, deafness and narcolepsy
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
hereditary sensory neuropathy-deafness-dementia syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet

DNMT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 19-10180405-T-C is Benign according to our data. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180405-T-C is described in CliVar as Likely_benign. Clinvar id is 539622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.17 with no splicing effect.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3 link	c.390A>G	p.Lys130Lys	synonymous_variant	Exon 4 of 41	ENST00000359526.9	NP_001124295.1	P26358-2I6L9H2
DNMT1	NM_001318730.2 link	c.390A>G	p.Lys130Lys	synonymous_variant	Exon 4 of 40		NP_001305659.1	P26358Q59FP7I6L9H2
DNMT1	NM_001379.4 link	c.390A>G	p.Lys130Lys	synonymous_variant	Exon 4 of 40		NP_001370.1	P26358-1I6L9H2
DNMT1	NM_001318731.2 link	c.27A>G	p.Lys9Lys	synonymous_variant	Exon 4 of 41		NP_001305660.1	P26358I6L9H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9 link	c.390A>G	p.Lys130Lys	synonymous_variant	Exon 4 of 41	1	NM_001130823.3	ENSP00000352516.3		P26358-2

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151938

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000155

AC:

AN:

251402

AF XY:

0.000155

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000121

AC:

177

AN:

1461764

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.0000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000148

AC:

165

AN:

1112012

Other (OTH)

AF:

0.0000993

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41478

American (AMR)

AF:

0.00

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67986

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000655

Hom.:

Bravo

AF:

0.0000756

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 04, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary sensory neuropathy-deafness-dementia syndrome

Benign:1

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.65

(source)

DANN

Benign

0.27

PhyloP100

-1.2

PromoterAI

-0.0094

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over