rs975957081

Variant names:

• chr19-10180186-C-A
• rs975957081
• NM_001130823.3:c.493+1G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10180186-C-A
• chr19-10180186-C-G
• chr19-10180186-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001130823.3(DNMT1):​c.493+1G>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 662,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: DNMT1 NM_001130823.3 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 0 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 Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)
• hereditary sensory neuropathy-deafness-dementia syndrome

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.009797918 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.4, offset of -16, new splice context is: caaGTaact. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.493+1G>T		splice_donor_variant, intron_variant	Intron 5 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.445+164G>T		intron_variant	Intron 4 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.445+164G>T		intron_variant	Intron 4 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.130+1G>T		splice_donor_variant, intron_variant	Intron 5 of 40		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.493+1G>T		splice_donor_variant, intron_variant	Intron 5 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000151 AC: 1 AN: 662720 Hom.: 0 Cov.: 9 AF XY: 0.00000286 AC XY: 1 AN XY: 349402

African (AFR) AF: 0.00 AC: 0 AN: 17696

American (AMR) AF: 0.00 AC: 0 AN: 33358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19540

East Asian (EAS) AF: 0.00 AC: 0 AN: 32040

South Asian (SAS) AF: 0.0000162 AC: 1 AN: 61894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 429630

Other (OTH) AF: 0.00 AC: 0 AN: 33754

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	18
DANN	Benign	0.59
Eigen	Benign	0.020
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.017	N
PhyloP100		1.2
GERP RS		-0.37
PromoterAI		-0.020	Neutral
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.64
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

Other links and lift over

dbSNP: rs975957081; hg19: chr19-10290862;