rs61750052

Variant names:

• chr19-10154368-G-A
• rs61750052
• NM_001130823.3:c.1944C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001130823.3(DNMT1):​c.1944C>T​(p.Phe648Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,614,236 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (38 hom.)
• Consequence: DNMT1 NM_001130823.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.07

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 19-10154368-G-A is Benign according to our data. Variant chr19-10154368-G-A is described in ClinVar as [Benign]. Clinvar id is 327907.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10154368-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.07 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00415 (6072/1461894) while in subpopulation SAS AF= 0.0172 (1481/86258). AF 95% confidence interval is 0.0164. There are 38 homozygotes in gnomad4_exome. There are 3283 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 436 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.1944C>T	p.Phe648Phe	synonymous_variant	Exon 22 of 41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.1896C>T	p.Phe632Phe	synonymous_variant	Exon 21 of 40		NP_001305659.1
DNMT1	NM_001379.4	c.1896C>T	p.Phe632Phe	synonymous_variant	Exon 21 of 40		NP_001370.1
DNMT1	NM_001318731.2	c.1581C>T	p.Phe527Phe	synonymous_variant	Exon 22 of 41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.1944C>T	p.Phe648Phe	synonymous_variant	Exon 22 of 41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.00286 AC: 436 AN: 152224 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00359

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00456 AC: 1146 AN: 251482 Hom.: 12 AF XY: 0.00517 AC XY: 703 AN XY: 135914

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00258

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0182

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00408

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00415 AC: 6072 AN: 1461894 Hom.: 38 Cov.: 31 AF XY: 0.00451 AC XY: 3283 AN XY: 727248

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.00168

Gnomad4 NFE exome AF: 0.00367

Gnomad4 OTH exome AF: 0.00430

GnomAD4 genome AF: 0.00286 AC: 436 AN: 152342 Hom.: 4 Cov.: 32 AF XY: 0.00298 AC XY: 222 AN XY: 74482

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00359

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00326 Hom.: 1

Bravo AF: 0.00259

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00367

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jul 01, 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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

not provided Benign:2

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 31, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: 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	-0.32
CADD	Benign	14
DANN	Benign	0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs61750052; hg19: chr19-10265044;