rs533403196

Variant names:

• chr19-10160072-A-G
• rs533403196
• NM_001130823.3:c.1044-9T>C

Your query was ambiguous. Multiple possible variants found:

• chr19-10160072-A-G
• chr19-10160072-A-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001130823.3(DNMT1):​c.1044-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000308 in 849,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: DNMT1 NM_001130823.3 intron
• Scores: Splicing: ADA: 0.00003916
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.505
• 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: 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-10160072-A-G is Benign according to our data. Variant chr19-10160072-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 539618.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 9 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.1044-9T>C		intron	N/A	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.996-9T>C		intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.996-9T>C		intron	N/A	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.1044-9T>C		intron	N/A	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.996-9T>C		intron	N/A	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000591764.1	TSL:1	n.222-9T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 9 AN: 8312 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00174

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000127 AC: 21 AN: 165822 AF XY: 0.000174

Gnomad AFR exome AF: 0.0000901

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000301 AC: 253 AN: 841370 Hom.: 0 Cov.: 33 AF XY: 0.000295 AC XY: 121 AN XY: 410680

African (AFR) AF: 0.0000747 AC: 1 AN: 13388

American (AMR) AF: 0.0000497 AC: 1 AN: 20106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12590

East Asian (EAS) AF: 0.00 AC: 0 AN: 9668

South Asian (SAS) AF: 0.0000626 AC: 2 AN: 31946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31862

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3338

European-Non Finnish (NFE) AF: 0.000351 AC: 241 AN: 686164

Other (OTH) AF: 0.000248 AC: 8 AN: 32308

GnomAD4 genome AF: 0.00108 AC: 9 AN: 8312 Hom.: 0 Cov.: 0 AF XY: 0.000718 AC XY: 3 AN XY: 4178

African (AFR) AF: 0.00360 AC: 1 AN: 278

American (AMR) AF: 0.00 AC: 0 AN: 1512

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 164

East Asian (EAS) AF: 0.00 AC: 0 AN: 114

South Asian (SAS) AF: 0.00 AC: 0 AN: 226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00174 AC: 8 AN: 4610

Other (OTH) AF: 0.00 AC: 0 AN: 98

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.0000869

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary sensory neuropathy-deafness-dementia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.5
DANN	Benign	0.39
PhyloP100		-0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.012
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: rs533403196; hg19: chr19-10270748;