rs2228612

Variant names:

• chr19-10162696-T-C
• rs2228612
• NM_001130823.3:c.979A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-10162696-T-C
• chr19-10162696-T-A
• chr19-10162696-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001130823.3(DNMT1):​c.979A>G​(p.Ile327Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0919 in 1,612,042 control chromosomes in the GnomAD database, including 10,725 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. I327M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1399 hom., cov: 30)
  • Exomes 𝑓: 0.090 (9326 hom.)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.726
• Publications: 85 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.05633E-4).
• BP6: Variant 19-10162696-T-C is Benign according to our data. Variant chr19-10162696-T-C is described in ClinVar as Benign. ClinVar VariationId is 137133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 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.979A>G	p.Ile327Val	missense	Exon 13 of 41	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.931A>G	p.Ile311Val	missense	Exon 12 of 40	NP_001305659.1
	DNMT1	NM_001379.4		c.931A>G	p.Ile311Val	missense	Exon 12 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.979A>G	p.Ile327Val	missense	Exon 13 of 41	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.931A>G	p.Ile311Val	missense	Exon 12 of 40	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000591764.1	TSL:1	n.157A>G		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.112 AC: 16950 AN: 150828 Hom.: 1396 Cov.: 30

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0717

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.0914

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0628

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.138 AC: 34795 AN: 251374 AF XY: 0.136

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.234

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.423

Gnomad FIN exome AF: 0.0872

Gnomad NFE exome AF: 0.0609

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.0898 AC: 131226 AN: 1461114 Hom.: 9326 Cov.: 36 AF XY: 0.0926 AC XY: 67295 AN XY: 726838

African (AFR) AF: 0.131 AC: 4376 AN: 33450

American (AMR) AF: 0.231 AC: 10315 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2924 AN: 26114

East Asian (EAS) AF: 0.367 AC: 14571 AN: 39674

South Asian (SAS) AF: 0.198 AC: 17044 AN: 86238

European-Finnish (FIN) AF: 0.0854 AC: 4553 AN: 53322

Middle Eastern (MID) AF: 0.0876 AC: 505 AN: 5768

European-Non Finnish (NFE) AF: 0.0634 AC: 70424 AN: 1111478

Other (OTH) AF: 0.108 AC: 6514 AN: 60364

GnomAD4 genome AF: 0.113 AC: 16985 AN: 150928 Hom.: 1399 Cov.: 30 AF XY: 0.119 AC XY: 8735 AN XY: 73698

African (AFR) AF: 0.126 AC: 5161 AN: 41068

American (AMR) AF: 0.190 AC: 2879 AN: 15142

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 375 AN: 3456

East Asian (EAS) AF: 0.398 AC: 2043 AN: 5132

South Asian (SAS) AF: 0.209 AC: 1000 AN: 4786

European-Finnish (FIN) AF: 0.0914 AC: 935 AN: 10228

Middle Eastern (MID) AF: 0.110 AC: 32 AN: 292

European-Non Finnish (NFE) AF: 0.0629 AC: 4266 AN: 67826

Other (OTH) AF: 0.109 AC: 229 AN: 2092

Alfa AF: 0.0842 Hom.: 2840

Bravo AF: 0.122

TwinsUK AF: 0.0620 AC: 230

ALSPAC AF: 0.0643 AC: 248

ESP6500AA AF: 0.128 AC: 562

ESP6500EA AF: 0.0651 AC: 560

ExAC AF: 0.132 AC: 16020

Asia WGS AF: 0.262 AC: 911 AN: 3478

EpiCase AF: 0.0658

EpiControl AF: 0.0659

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Hereditary sensory neuropathy-deafness-dementia syndrome (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.22
DANN	Benign	0.20
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0031	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.00091	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.73
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.013
MPC		0.34
ClinPred		0.000013	T
GERP RS		-4.7
Varity_R		0.0098
gMVP		0.042
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2228612; hg19: chr19-10273372; COSMIC: COSV61579616; COSMIC: COSV61579616;