NM_001130823.3:c.4293+238C>G

Variant names:

• chr19-10137594-G-C
• rs10854076
• NM_001130823.3:c.4293+238C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130823.3(DNMT1):​c.4293+238C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 663,284 control chromosomes in the GnomAD database, including 6,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1365 hom., cov: 32)
  • Exomes 𝑓: 0.11 (4843 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.16
• Publications: 7 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=-0.9).
• BP6: Variant 19-10137594-G-C is Benign according to our data. Variant chr19-10137594-G-C is described in ClinVar as Benign. ClinVar VariationId is 1293062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.4293+238C>G		intron_variant	Intron 36 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.4245+238C>G		intron_variant	Intron 35 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.4245+238C>G		intron_variant	Intron 35 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.3930+238C>G		intron_variant	Intron 36 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.4293+238C>G		intron_variant	Intron 36 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16766 AN: 152014 Hom.: 1362 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.393

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0927

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0624

Gnomad OTH AF: 0.108

GnomAD4 exome AF: 0.107 AC: 54921 AN: 511152 Hom.: 4843 Cov.: 6 AF XY: 0.112 AC XY: 29997 AN XY: 268794

African (AFR) AF: 0.123 AC: 1729 AN: 14072

American (AMR) AF: 0.214 AC: 4947 AN: 23094

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 1623 AN: 14676

East Asian (EAS) AF: 0.352 AC: 11086 AN: 31516

South Asian (SAS) AF: 0.196 AC: 9543 AN: 48764

European-Finnish (FIN) AF: 0.0828 AC: 2484 AN: 29986

Middle Eastern (MID) AF: 0.0859 AC: 185 AN: 2154

European-Non Finnish (NFE) AF: 0.0632 AC: 20146 AN: 318574

Other (OTH) AF: 0.112 AC: 3178 AN: 28316

GnomAD4 genome AF: 0.110 AC: 16798 AN: 152132 Hom.: 1365 Cov.: 32 AF XY: 0.116 AC XY: 8658 AN XY: 74380

African (AFR) AF: 0.120 AC: 4979 AN: 41518

American (AMR) AF: 0.187 AC: 2858 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3470

East Asian (EAS) AF: 0.394 AC: 2029 AN: 5156

South Asian (SAS) AF: 0.208 AC: 1003 AN: 4828

European-Finnish (FIN) AF: 0.0927 AC: 983 AN: 10606

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0625 AC: 4247 AN: 67994

Other (OTH) AF: 0.108 AC: 228 AN: 2108

Alfa AF: 0.0201 Hom.: 6

Bravo AF: 0.119

Asia WGS AF: 0.258 AC: 899 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 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	-0.90
CADD	Benign	0.25
DANN	Benign	0.49
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs10854076; hg19: chr19-10248270; COSMIC: COSV61585077; COSMIC: COSV61585077;