19-10194822-C-T

Variant names:

• chr19-10194822-C-T
• rs780503694
• NM_001130823.3:c.78G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_001130823.3(DNMT1):​c.78G>A​(p.Arg26Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 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: 32)
• Consequence: DNMT1 NM_001130823.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0007798
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.77
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP7: Synonymous conserved (PhyloP=1.77 with no splicing effect.

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.78G>A	p.Arg26Arg	splice_region synonymous	Exon 1 of 41	NP_001124295.1
	DNMT1	NM_001318731.2		c.-246G>A		splice_region	Exon 1 of 41	NP_001305660.1
	DNMT1	NM_001318730.2		c.78G>A	p.Arg26Arg	splice_region synonymous	Exon 1 of 40	NP_001305659.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNMT1	ENST00000359526.9	TSL:1 MANE Select	c.78G>A	p.Arg26Arg	splice_region synonymous	Exon 1 of 41	ENSP00000352516.3
	DNMT1	ENST00000340748.8	TSL:1	c.78G>A	p.Arg26Arg	splice_region synonymous	Exon 1 of 40	ENSP00000345739.3
	DNMT1	ENST00000592705.5	TSL:1	n.78G>A		splice_region non_coding_transcript_exon	Exon 1 of 41	ENSP00000466657.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000623 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.92
PhyloP100		1.8
PromoterAI		0.051	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00078
dbscSNV1_RF	Benign	0.0040
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: rs780503694; hg19: chr19-10305498;