rs75443147

Variant names:

• chr19-10155049-G-A
• rs75443147
• NM_001130823.3:c.1500C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10155049-G-A
• chr19-10155049-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001130823.3(DNMT1):​c.1500C>T​(p.Ala500Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,614,048 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (19 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (116 hom.)
• Consequence: DNMT1 NM_001130823.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.79

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 19-10155049-G-A is Benign according to our data. Variant chr19-10155049-G-A is described in ClinVar as [Benign]. Clinvar id is 327910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10155049-G-A is described in Lovd as [Likely_benign]. Variant chr19-10155049-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00585 (890/152244) while in subpopulation EAS AF= 0.0342 (177/5178). AF 95% confidence interval is 0.0301. There are 19 homozygotes in gnomad4. There are 587 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 890 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.1500C>T	p.Ala500Ala	synonymous_variant	Exon 20 of 41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.1452C>T	p.Ala484Ala	synonymous_variant	Exon 19 of 40		NP_001305659.1
DNMT1	NM_001379.4	c.1452C>T	p.Ala484Ala	synonymous_variant	Exon 19 of 40		NP_001370.1
DNMT1	NM_001318731.2	c.1137C>T	p.Ala379Ala	synonymous_variant	Exon 20 of 41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.1500C>T	p.Ala500Ala	synonymous_variant	Exon 20 of 41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.00586 AC: 891 AN: 152126 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0341

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00148

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00874 AC: 2198 AN: 251412 Hom.: 41 AF XY: 0.00859 AC XY: 1167 AN XY: 135878

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0329

Gnomad SAS exome AF: 0.00924

Gnomad FIN exome AF: 0.0491

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.00863

GnomAD4 exome AF: 0.00389 AC: 5687 AN: 1461804 Hom.: 116 Cov.: 36 AF XY: 0.00395 AC XY: 2872 AN XY: 727206

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0354

Gnomad4 SAS exome AF: 0.00856

Gnomad4 FIN exome AF: 0.0443

Gnomad4 NFE exome AF: 0.000612

Gnomad4 OTH exome AF: 0.00760

GnomAD4 genome AF: 0.00585 AC: 890 AN: 152244 Hom.: 19 Cov.: 32 AF XY: 0.00789 AC XY: 587 AN XY: 74426

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0342

Gnomad4 SAS AF: 0.00787

Gnomad4 FIN AF: 0.0475

Gnomad4 NFE AF: 0.00148

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00183 Hom.: 1

Bravo AF: 0.00194

Asia WGS AF: 0.0470 AC: 164 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 15, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 25, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:2

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.051
DANN	Benign	0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs75443147; hg19: chr19-10265725;