rs975957081

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PVS1_ModerateBP6_Very_StrongBS2

The NM_001130823.3(DNMT1):c.493+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 814,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000075 ( 0 hom. )

Consequence

DNMT1
NM_001130823.3 splice_donor, intron

Scores

Splicing: ADA: 0.9999

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.17

Publications

0 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: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
hereditary sensory neuropathy-deafness-dementia syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: 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 -10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.009797918 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.4, offset of -16, new splice context is: caaGTaact. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 19-10180186-C-T is Benign according to our data. Variant chr19-10180186-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 472278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 33 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	Effect	Exon Rank	Protein	UniProt
DNMT1	NM_001130823.3	MANE Select	c.493+1G>A	splice_donor intron	N/A	NP_001124295.1	P26358-2
DNMT1	NM_001318730.2		c.445+164G>A	intron	N/A	NP_001305659.1
DNMT1	NM_001379.4		c.445+164G>A	intron	N/A	NP_001370.1	P26358-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.493+1G>A	splice_donor intron	N/A	ENSP00000352516.3	P26358-2
DNMT1	ENST00000340748.8	TSL:1	c.445+164G>A	intron	N/A	ENSP00000345739.3	P26358-1
DNMT1	ENST00000590619.1	TSL:1	c.79+1G>A	splice_donor intron	N/A	ENSP00000468062.1	K7ER10

Frequencies

GnomAD3 genomes

AF:

0.000218

AC:

AN:

151694

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0275

Gnomad AMR

AF:

0.000263

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:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000211

AC:

AN:

123342

AF XY:

0.000225

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000428

Gnomad OTH exome

AF:

0.000783

GnomAD4 exome

AF:

0.0000754

AC:

AN:

662720

Hom.:

Cov.:

AF XY:

0.0000716

AC XY:

AN XY:

349402

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17696

American (AMR)

AF:

0.000809

AC:

AN:

33358

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19540

East Asian (EAS)

AF:

0.00

AC:

AN:

32040

South Asian (SAS)

AF:

0.00

AC:

AN:

61894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2644

European-Non Finnish (NFE)

AF:

0.0000466

AC:

AN:

429630

Other (OTH)

AF:

0.0000889

AC:

AN:

33754

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:

0.000218

AC:

AN:

151694

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74080

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41254

American (AMR)

AF:

0.000263

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67942

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.00

Hom.:

Bravo

AF:

0.000287

ClinVar

ClinVar submissions

Significance:Likely 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_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.90

CADD

Benign

(source)

DANN

Benign

0.59

Eigen

Benign

0.020

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.011

PhyloP100

1.2

GERP RS

-0.37

PromoterAI

-0.016

Neutral

(source)

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.63

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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