rs75616428

Positions:

• chr19-10180437-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001130823.3(DNMT1):​c.358G>C​(p.Val120Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,614,188 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (79 hom.)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.540

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.

• 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=0.0021920502).
• BP6: Variant 19-10180437-C-G is Benign according to our data. Variant chr19-10180437-C-G is described in ClinVar as [Benign]. Clinvar id is 327927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10180437-C-G is described in Lovd as [Benign]. Variant chr19-10180437-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0579 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.358G>C	p.Val120Leu	missense_variant	4/41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.358G>C	p.Val120Leu	missense_variant	4/40		NP_001305659.1
DNMT1	NM_001379.4	c.358G>C	p.Val120Leu	missense_variant	4/40		NP_001370.1
DNMT1	NM_001318731.2	c.-6G>C		5_prime_UTR_variant	4/41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.358G>C	p.Val120Leu	missense_variant	4/41	1	NM_001130823.3	ENSP00000352516

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 416 AN: 152180 Hom.: 10 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.0547

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00627 AC: 1576 AN: 251482 Hom.: 46 AF XY: 0.00586 AC XY: 796 AN XY: 135920

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.0695

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00638

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.00358

GnomAD4 exome AF: 0.00237 AC: 3462 AN: 1461890 Hom.: 79 Cov.: 30 AF XY: 0.00239 AC XY: 1737 AN XY: 727248

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00597

Gnomad4 EAS exome AF: 0.0599

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.00680

Gnomad4 NFE exome AF: 0.000258

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00272 AC: 415 AN: 152298 Hom.: 9 Cov.: 31 AF XY: 0.00340 AC XY: 253 AN XY: 74462

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.0546

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00259 Hom.: 8

Bravo AF: 0.00340

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00603 AC: 732

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.8
DANN	Benign	0.96
DEOGEN2	Benign	0.38	T;.;T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.74	T;T;T
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.49	N;N;.
REVEL	Benign	0.024
Sift	Benign	0.12	T;T;.
Sift4G	Benign	0.33	T;T;D
Polyphen		0.17	B;B;.
Vest4		0.17
MutPred		0.27		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);.;
MVP		0.42
MPC		0.47
ClinPred		0.0021	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.18

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: rs75616428; hg19: chr19-10291113;