rs61758431

Positions:

• chr19-10162694-A-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001130823.3(DNMT1):​c.981T>G​(p.Ile327Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000313 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I327V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.64

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DNMT1. . Gene score misZ 4.9903 (greater than the threshold 3.09). Trascript score misZ 7.3302 (greater than threshold 3.09). GenCC has associacion of gene with hereditary sensory neuropathy-deafness-dementia syndrome, autosomal dominant cerebellar ataxia, deafness and narcolepsy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009596407).
• BP6: Variant 19-10162694-A-C is Benign according to our data. Variant chr19-10162694-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 327918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.981T>G	p.Ile327Met	missense_variant	13/41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.933T>G	p.Ile311Met	missense_variant	12/40		NP_001305659.1
DNMT1	NM_001379.4	c.933T>G	p.Ile311Met	missense_variant	12/40		NP_001370.1
DNMT1	NM_001318731.2	c.618T>G	p.Ile206Met	missense_variant	13/41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.981T>G	p.Ile327Met	missense_variant	13/41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 151904 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000857

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000473 AC: 119 AN: 251436 Hom.: 0 AF XY: 0.000471 AC XY: 64 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.000607

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000306 AC: 448 AN: 1461830 Hom.: 0 Cov.: 34 AF XY: 0.000311 AC XY: 226 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00367

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000899

Gnomad4 NFE exome AF: 0.000254

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000375 AC: 57 AN: 152016 Hom.: 0 Cov.: 31 AF XY: 0.000417 AC XY: 31 AN XY: 74332

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000857

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000599 Hom.: 0

Bravo AF: 0.000257

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000502 AC: 61

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 29, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	DNMT1: PP2, BP4, BS2 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.57
DANN	Benign	0.54
DEOGEN2	Benign	0.39	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.53	T;T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.0096	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.34	N;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.12
Sift	Benign	0.093	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0	B;B
Vest4		0.061
MVP		0.46
MPC		0.42
ClinPred		0.019	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.048

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61758431; hg19: chr19-10273370; COSMIC: COSV61583705; COSMIC: COSV61583705;