dbSNP rs2229858: DNMT1:p.Pro1456Pro (chr19-10137206-G-A) – ACMG Classification: Benign (-17 pts)

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.4368C>T(p.Pro1456Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,611,064 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 Benign (★★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

DNMT1
NM_001130823.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.11

Publications

1 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, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, PanelApp Australia, Genomics England PanelApp
hereditary sensory neuropathy-deafness-dementia syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

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=-0.67).

BP6

Variant 19-10137206-G-A is Benign according to our data. Variant chr19-10137206-G-A is described in ClinVar as Benign. ClinVar VariationId is 472276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.11 with no splicing effect.

BS2

High AC in GnomAd4 at 142 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130823.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNMT1	NM_001130823.3	MANE Select	c.4368C>T	p.Pro1456Pro	synonymous	Exon 37 of 41	NP_001124295.1	P26358-2
DNMT1	NM_001318730.2		c.4320C>T	p.Pro1440Pro	synonymous	Exon 36 of 40	NP_001305659.1
DNMT1	NM_001379.4		c.4320C>T	p.Pro1440Pro	synonymous	Exon 36 of 40	NP_001370.1	P26358-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.4368C>T	p.Pro1456Pro	synonymous	Exon 37 of 41	ENSP00000352516.3	P26358-2
DNMT1	ENST00000340748.8	TSL:1	c.4320C>T	p.Pro1440Pro	synonymous	Exon 36 of 40	ENSP00000345739.3	P26358-1
DNMT1	ENST00000592705.5	TSL:1	n.*4058C>T		non_coding_transcript_exon	Exon 37 of 41	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes

AF:

0.000933

AC:

142

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000214

AC:

AN:

242856

AF XY:

0.000174

show subpopulations

Gnomad AFR exome

AF:

0.00274

Gnomad AMR exome

AF:

0.000206

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000273

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000877

AC:

128

AN:

1458700

Hom.:

Cov.:

AF XY:

0.0000703

AC XY:

AN XY:

725382

show subpopulations

African (AFR)

AF:

0.00308

AC:

103

AN:

33454

American (AMR)

AF:

0.000158

AC:

AN:

44366

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.00

AC:

AN:

39632

South Asian (SAS)

AF:

0.00

AC:

AN:

85622

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52492

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111214

Other (OTH)

AF:

0.000199

AC:

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.000932

AC:

142

AN:

152364

Hom.:

Cov.:

AF XY:

0.000926

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00325

AC:

135

AN:

41580

American (AMR)

AF:

0.000261

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000822

Hom.:

Bravo

AF:

0.00102

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary sensory neuropathy-deafness-dementia syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.4

(source)

DANN

Benign

0.70

PhyloP100

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over