rs148831705

chr19-10163333-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_001130823.3(DNMT1):c.919A>G(p.Lys307Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,613,902 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.967

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DNMT1
• BP4: Computational evidence support a benign effect (MetaRNN=0.11368513).
• BP6: Variant 19-10163333-T-C is Benign according to our data. Variant chr19-10163333-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 234681.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}. Variant chr19-10163333-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.919A>G	p.Lys307Glu	missense_variant	12/41	ENST00000359526.9
DNMT1	NM_001318730.2	c.871A>G	p.Lys291Glu	missense_variant	11/40
DNMT1	NM_001379.4	c.871A>G	p.Lys291Glu	missense_variant	11/40
DNMT1	NM_001318731.2	c.556A>G	p.Lys186Glu	missense_variant	12/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.919A>G	p.Lys307Glu	missense_variant	12/41	1	NM_001130823.3

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152178 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000478 AC: 12 AN: 251296 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135868

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152178 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74346

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2021	This variant is associated with the following publications: (PMID: no PMID) -

DNMT1-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2022

The DNMT1 c.919A>G variant is predicted to result in the amino acid substitution p.Lys307Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-10274009-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary sensory neuropathy-deafness-dementia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 25, 2023

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 307 of the DNMT1 protein (p.Lys307Glu). This variant is present in population databases (rs148831705, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with DNMT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 234681). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.13
Sift	Benign	0.089	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0040	B;B
Vest4		0.27
MVP		0.67
MPC		0.65
ClinPred		0.031	T
GERP RS		3.4
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.1
Varity_R		0.053
gMVP		0.059

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: rs148831705; hg19: chr19-10274009; COSMIC: COSV61584882; COSMIC: COSV61584882;