19-10156401-T-C

Variant names:

• chr19-10156401-T-C
• rs2228611
• NM_001130823.3:c.1389A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001130823.3(DNMT1):​c.1389A>G​(p.Pro463Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.504 in 1,605,870 control chromosomes in the GnomAD database, including 205,839 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P463P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.51 (19965 hom., cov: 29)
  • Exomes 𝑓: 0.50 (185874 hom.)
• Consequence: DNMT1 NM_001130823.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -8.10
• Publications: 115 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: Unknown, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 19-10156401-T-C is Benign according to our data. Variant chr19-10156401-T-C is described in ClinVar as Benign. ClinVar VariationId is 257536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

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.1389A>G	p.Pro463Pro	synonymous	Exon 18 of 41	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.1341A>G	p.Pro447Pro	synonymous	Exon 17 of 40	NP_001305659.1
	DNMT1	NM_001379.4		c.1341A>G	p.Pro447Pro	synonymous	Exon 17 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.1389A>G	p.Pro463Pro	synonymous	Exon 18 of 41	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.1341A>G	p.Pro447Pro	synonymous	Exon 17 of 40	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000592705.5	TSL:1	n.*1079A>G		non_coding_transcript_exon	Exon 18 of 41	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77266 AN: 151414 Hom.: 19932 Cov.: 29

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.556

Gnomad EAS AF: 0.674

Gnomad SAS AF: 0.547

Gnomad FIN AF: 0.515

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.497

Gnomad OTH AF: 0.487

GnomAD2 exomes AF: 0.519 AC: 130376 AN: 251354 AF XY: 0.518

Gnomad AFR exome AF: 0.512

Gnomad AMR exome AF: 0.484

Gnomad ASJ exome AF: 0.552

Gnomad EAS exome AF: 0.695

Gnomad FIN exome AF: 0.521

Gnomad NFE exome AF: 0.493

Gnomad OTH exome AF: 0.513

GnomAD4 exome AF: 0.504 AC: 732721 AN: 1454336 Hom.: 185874 Cov.: 30 AF XY: 0.505 AC XY: 365549 AN XY: 723916

African (AFR) AF: 0.510 AC: 16964 AN: 33280

American (AMR) AF: 0.482 AC: 21517 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 14417 AN: 26010

East Asian (EAS) AF: 0.622 AC: 24593 AN: 39538

South Asian (SAS) AF: 0.537 AC: 46259 AN: 86116

European-Finnish (FIN) AF: 0.524 AC: 27766 AN: 53010

Middle Eastern (MID) AF: 0.562 AC: 3222 AN: 5736

European-Non Finnish (NFE) AF: 0.495 AC: 547238 AN: 1106008

Other (OTH) AF: 0.512 AC: 30745 AN: 60032

GnomAD4 genome AF: 0.511 AC: 77363 AN: 151534 Hom.: 19965 Cov.: 29 AF XY: 0.512 AC XY: 37910 AN XY: 74036

African (AFR) AF: 0.509 AC: 21025 AN: 41316

American (AMR) AF: 0.493 AC: 7492 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.556 AC: 1927 AN: 3468

East Asian (EAS) AF: 0.675 AC: 3453 AN: 5118

South Asian (SAS) AF: 0.547 AC: 2614 AN: 4782

European-Finnish (FIN) AF: 0.515 AC: 5393 AN: 10462

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.497 AC: 33763 AN: 67896

Other (OTH) AF: 0.491 AC: 1031 AN: 2098

Alfa AF: 0.500 Hom.: 84013

Bravo AF: 0.505

Asia WGS AF: 0.603 AC: 2096 AN: 3478

EpiCase AF: 0.491

EpiControl AF: 0.487

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Hereditary sensory neuropathy-deafness-dementia syndrome (3)
-	-	2	not provided (2)
-	-	1	Autosomal dominant cerebellar ataxia, deafness and narcolepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.31
DANN	Benign	0.36
PhyloP100		-8.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2228611; hg19: chr19-10267077; COSMIC: COSV61577791; COSMIC: COSV61577791;