19-10180797-C-T

Variant names:

• chr19-10180797-C-T
• rs61750053
• NM_001130823.3:c.206G>A
• DNMT1 p.Arg69His

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001130823.3(DNMT1):​c.206G>A​(p.Arg69His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,613,950 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0094 (9 hom., cov: 31)
  • Exomes 𝑓: 0.011 (113 hom.)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.392
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant cerebellar ataxia, deafness and narcolepsy

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, ClinGen
• hereditary sensory neuropathy-deafness-dementia syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023405552).
• BP6: Variant 19-10180797-C-T is Benign according to our data. Variant chr19-10180797-C-T is described in ClinVar as Benign. ClinVar VariationId is 137132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1424 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130823.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	NM_001130823.3	MANE Select	c.206G>A	p.Arg69His	missense	Exon 3 of 41	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.206G>A	p.Arg69His	missense	Exon 3 of 40	NP_001305659.1
	DNMT1	NM_001379.4		c.206G>A	p.Arg69His	missense	Exon 3 of 40	NP_001370.1	P26358-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.206G>A	p.Arg69His	missense	Exon 3 of 41	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.206G>A	p.Arg69His	missense	Exon 3 of 40	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000592705.5	TSL:1	n.206G>A		non_coding_transcript_exon	Exon 3 of 41	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes AF: 0.00936 AC: 1423 AN: 152102 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00302

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.0312

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.0101 AC: 2549 AN: 251240 AF XY: 0.0101

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0316

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0113 AC: 16539 AN: 1461730 Hom.: 113 Cov.: 31 AF XY: 0.0111 AC XY: 8049 AN XY: 727186

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00291 AC: 130 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0183 AC: 479 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00260 AC: 224 AN: 86256

European-Finnish (FIN) AF: 0.0299 AC: 1597 AN: 53394

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5762

European-Non Finnish (NFE) AF: 0.0121 AC: 13500 AN: 1111894

Other (OTH) AF: 0.00924 AC: 558 AN: 60388

GnomAD4 genome AF: 0.00935 AC: 1424 AN: 152220 Hom.: 9 Cov.: 31 AF XY: 0.00956 AC XY: 712 AN XY: 74442

African (AFR) AF: 0.00200 AC: 83 AN: 41562

American (AMR) AF: 0.00301 AC: 46 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.00374 AC: 18 AN: 4814

European-Finnish (FIN) AF: 0.0312 AC: 331 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0128 AC: 869 AN: 68000

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.0108 Hom.: 33

Bravo AF: 0.00700

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.00954

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	2	Hereditary sensory neuropathy-deafness-dementia syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.58
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N
PhyloP100		0.39
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.040
Sift	Benign	1.0	T
Sift4G	Benign	0.37	T
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.017
gMVP		0.046
Mutation Taster		=98/2	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61750053;

hg19: chr19-10291473;

COSMIC: COSV61577141;