rs755492225

Positions:

• chr19-10139723-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_001130823.3(DNMT1):​c.3901C>T​(p.Arg1301Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,282 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.59

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 -3 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.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.3901C>T	p.Arg1301Cys	missense_variant	34/41	ENST00000359526.9
DNMT1	NM_001318730.2	c.3853C>T	p.Arg1285Cys	missense_variant	33/40
DNMT1	NM_001379.4	c.3853C>T	p.Arg1285Cys	missense_variant	33/40
DNMT1	NM_001318731.2	c.3538C>T	p.Arg1180Cys	missense_variant	34/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.3901C>T	p.Arg1301Cys	missense_variant	34/41	1	NM_001130823.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000121 AC: 3 AN: 248204 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134494

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461282 Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10 AN XY: 726902

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 28, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1301 of the DNMT1 protein (p.Arg1301Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 571637). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Benign	0.064
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.3	L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.57
Sift	Benign	0.031	D;D
Sift4G	Benign	0.088	T;T
Polyphen		0.76	P;P
Vest4		0.57
MutPred		0.64		Loss of MoRF binding (P = 0.0011);.;
MVP		0.80
MPC		1.4
ClinPred		0.79	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.58
gMVP		0.96

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: rs755492225; hg19: chr19-10250399;