19-10162696-T-C

Position:

• chr19-10162696-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 15/20 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:8
• Conservation: PhyloP100: -0.726

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 Benign. Variant got -19 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.
• 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 id is 137133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-10162696-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.979A>G	p.Ile327Val	missense_variant	13/41	ENST00000359526.9
DNMT1	NM_001318730.2	c.931A>G	p.Ile311Val	missense_variant	12/40
DNMT1	NM_001379.4	c.931A>G	p.Ile311Val	missense_variant	12/40
DNMT1	NM_001318731.2	c.616A>G	p.Ile206Val	missense_variant	13/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.979A>G	p.Ile327Val	missense_variant	13/41	1	NM_001130823.3

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

GnomAD3 exomes AF: 0.138 AC: 34795 AN: 251374 Hom.: 3881 AF XY: 0.136 AC XY: 18442 AN XY: 135884

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 SAS exome AF: 0.206

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

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.231

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.367

Gnomad4 SAS exome AF: 0.198

Gnomad4 FIN exome AF: 0.0854

Gnomad4 NFE exome AF: 0.0634

Gnomad4 OTH exome AF: 0.108

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

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.190

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.398

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.0914

Gnomad4 NFE AF: 0.0629

Gnomad4 OTH AF: 0.109

Alfa AF: 0.0835 Hom.: 1510

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

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.00091	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.030	N;N
REVEL	Benign	0.18
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.013
MPC		0.34
ClinPred		0.000013	T
GERP RS		-4.7
Varity_R		0.0098
gMVP		0.042

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228612; hg19: chr19-10273372; COSMIC: COSV61579616; COSMIC: COSV61579616;