19-10134105-G-A

Variant names:

• chr19-10134105-G-A
• rs76159732
• NM_001130823.3:c.4864+112C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001130823.3(DNMT1):​c.4864+112C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,105,682 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (50 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (36 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.135
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-10134105-G-A is Benign according to our data. Variant chr19-10134105-G-A is described in ClinVar as [Benign]. Clinvar id is 1258099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2185/152352) while in subpopulation AFR AF = 0.0496 (2062/41586). AF 95% confidence interval is 0.0478. There are 50 homozygotes in GnomAd4. There are 1051 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2185 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.4864+112C>T		intron_variant	Intron 40 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.4825+112C>T		intron_variant	Intron 39 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.4816+112C>T		intron_variant	Intron 39 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.4501+112C>T		intron_variant	Intron 40 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.4864+112C>T		intron_variant	Intron 40 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2181 AN: 152234 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0496

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.0110

GnomAD4 exome AF: 0.00147 AC: 1401 AN: 953330 Hom.: 36 AF XY: 0.00117 AC XY: 579 AN XY: 494282

African (AFR) AF: 0.0487 AC: 1135 AN: 23318

American (AMR) AF: 0.00244 AC: 102 AN: 41784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22296

East Asian (EAS) AF: 0.00 AC: 0 AN: 36992

South Asian (SAS) AF: 0.0000807 AC: 6 AN: 74324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49880

Middle Eastern (MID) AF: 0.00147 AC: 7 AN: 4776

European-Non Finnish (NFE) AF: 0.0000411 AC: 27 AN: 656378

Other (OTH) AF: 0.00285 AC: 124 AN: 43582

GnomAD4 genome AF: 0.0143 AC: 2185 AN: 152352 Hom.: 50 Cov.: 32 AF XY: 0.0141 AC XY: 1051 AN XY: 74502

African (AFR) AF: 0.0496 AC: 2062 AN: 41586

American (AMR) AF: 0.00621 AC: 95 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68034

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.00792 Hom.: 6

Bravo AF: 0.0159

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.0
DANN	Benign	0.71
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs76159732; hg19: chr19-10244781;