rs533403196

chr19-10160072-A-Gchr19-10160072-A-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001130823.3(DNMT1):c.1044-9T>C variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003916
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.505

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 -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 id is 539618.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNMT1	NM_001130823.3	c.1044-9T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000359526.9
DNMT1	NM_001318730.2	c.996-9T>C		splice_polypyrimidine_tract_variant, intron_variant
DNMT1	NM_001318731.2	c.681-9T>C		splice_polypyrimidine_tract_variant, intron_variant
DNMT1	NM_001379.4	c.996-9T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNMT1	ENST00000359526.9	c.1044-9T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001130823.3

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

GnomAD3 exomes AF: 0.000127 AC: 21 AN: 165822 Hom.: 0 AF XY: 0.000174 AC XY: 16 AN XY: 91744

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 SAS exome AF: 0.0000436

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

Gnomad4 AFR exome AF: 0.0000747

Gnomad4 AMR exome AF: 0.0000497

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000626

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000351

Gnomad4 OTH exome AF: 0.000248

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

Gnomad4 AFR AF: 0.00360

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00174

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000270 Hom.: 0

Bravo AF: 0.0000869

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.5
Dann	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs533403196; hg19: chr19-10270748;