chr19-10180180-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001130823.3(DNMT1):c.493+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000387 in 775,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000032 ( 0 hom. )

Consequence

DNMT1
NM_001130823.3 splice_region, intron

Scores

Splicing: ADA: 0.00001752

Clinical Significance

Likely benign criteria provided, single submitter B:1

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: 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: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 19-10180180-C-T is Benign according to our data. Variant chr19-10180180-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 539612.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3 link	c.493+7G>A	splice_region_variant, intron_variant	Intron 5 of 40	ENST00000359526.9	NP_001124295.1	P26358-2I6L9H2
DNMT1	NM_001318730.2 link	c.445+170G>A	intron_variant	Intron 4 of 39		NP_001305659.1	P26358Q59FP7I6L9H2
DNMT1	NM_001379.4 link	c.445+170G>A	intron_variant	Intron 4 of 39		NP_001370.1	P26358-1I6L9H2
DNMT1	NM_001318731.2 link	c.130+7G>A	splice_region_variant, intron_variant	Intron 5 of 40		NP_001305660.1	P26358I6L9H2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9 link	c.493+7G>A		splice_region_variant, intron_variant	Intron 5 of 40	1	NM_001130823.3	ENSP00000352516.3		P26358-2

Frequencies

GnomAD3 genomes

AF:

0.00000666

AC:

AN:

150254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

117140

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000320

AC:

AN:

625618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

330460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16856

American (AMR)

AF:

0.00

AC:

AN:

32222

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18840

East Asian (EAS)

AF:

0.00

AC:

AN:

31588

South Asian (SAS)

AF:

0.00

AC:

AN:

60008

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2544

European-Non Finnish (NFE)

AF:

0.00000500

AC:

AN:

399820

Other (OTH)

AF:

0.00

AC:

AN:

32296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00000666

AC:

AN:

150254

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73272

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40740

American (AMR)

AF:

0.00

AC:

AN:

15018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.00

AC:

AN:

5080

South Asian (SAS)

AF:

0.00

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

304

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67568

Other (OTH)

AF:

0.00

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000509

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome

Benign:1

Oct 22, 2017

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

-0.90

CADD

Benign

3.9

(source)

DANN

Benign

0.29

PhyloP100

1.2

PromoterAI

0.0042

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

dbscSNV1_RF

Benign

0.058

SpliceAI score (max)

0.15

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over