rs61758430

Variant names:

• chr19-10163327-G-C
• rs61758430
• NM_001130823.3:c.925C>G

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.925C>G​(p.Leu309Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000507 in 1,613,922 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L309I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: DNMT1 NM_001130823.3 missense, splice_region
• Scores: Splicing: ADA: 0.0002421
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.966
• Publications: 4 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00642398).
• BP6: Variant 19-10163327-G-C is Benign according to our data. Variant chr19-10163327-G-C is described in ClinVar as Benign. ClinVar VariationId is 389881.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 421 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.925C>G	p.Leu309Val	missense splice_region	Exon 12 of 41	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.877C>G	p.Leu293Val	missense splice_region	Exon 11 of 40	NP_001305659.1
	DNMT1	NM_001379.4		c.877C>G	p.Leu293Val	missense splice_region	Exon 11 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.925C>G	p.Leu309Val	missense splice_region	Exon 12 of 41	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.877C>G	p.Leu293Val	missense splice_region	Exon 11 of 40	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000591764.1	TSL:1	n.103C>G		splice_region non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.00276 AC: 420 AN: 152136 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.00961

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000984

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000752 AC: 189 AN: 251286 AF XY: 0.000581

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000272 AC: 397 AN: 1461668 Hom.: 2 Cov.: 31 AF XY: 0.000231 AC XY: 168 AN XY: 727134

African (AFR) AF: 0.00872 AC: 292 AN: 33474

American (AMR) AF: 0.000380 AC: 17 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111940

Other (OTH) AF: 0.000712 AC: 43 AN: 60388

GnomAD4 genome AF: 0.00277 AC: 421 AN: 152254 Hom.: 3 Cov.: 31 AF XY: 0.00263 AC XY: 196 AN XY: 74440

African (AFR) AF: 0.00960 AC: 399 AN: 41546

American (AMR) AF: 0.000982 AC: 15 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000408 Hom.: 0

Bravo AF: 0.00307

ESP6500AA AF: 0.0104 AC: 46

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000972 AC: 118

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary sensory neuropathy-deafness-dementia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.97
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.16
Sift	Benign	0.31	T
Sift4G	Benign	0.97	T
Polyphen		0.89	P
Vest4		0.18
MVP		0.82
MPC		0.42
ClinPred		0.017	T
GERP RS		1.9
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.1
Varity_R		0.030
gMVP		0.075
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.040		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: rs61758430; hg19: chr19-10274003;