19-10137594-G-C

Position:

• chr19-10137594-G-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.4293+238C>G		intron_variant		ENST00000359526.9
DNMT1	NM_001318730.2	c.4245+238C>G		intron_variant
DNMT1	NM_001318731.2	c.3930+238C>G		intron_variant
DNMT1	NM_001379.4	c.4245+238C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.4293+238C>G		intron_variant		1	NM_001130823.3

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

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.352

Gnomad4 SAS exome AF: 0.196

Gnomad4 FIN exome AF: 0.0828

Gnomad4 NFE exome AF: 0.0632

Gnomad4 OTH exome AF: 0.112

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

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.108

Gnomad4 EAS AF: 0.394

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.0927

Gnomad4 NFE AF: 0.0625

Gnomad4 OTH AF: 0.108

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.25
DANN	Benign	0.49

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

Publications

LitVar

Other links and lift over

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