19-10180186-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PVS1_Moderate BP6_Very_Strong BS2

The NM_001130823.3(DNMT1):​c.493+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 814,414 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. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: DNMT1 NM_001130823.3 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.17

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.

• 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.
• BP6: Variant 19-10180186-C-T is Benign according to our data. Variant chr19-10180186-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 472278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.493+1G>A		splice_donor_variant, intron_variant	Intron 5 of 40	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.445+164G>A		intron_variant	Intron 4 of 39		NP_001305659.1
DNMT1	NM_001379.4	c.445+164G>A		intron_variant	Intron 4 of 39		NP_001370.1
DNMT1	NM_001318731.2	c.130+1G>A		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>A		splice_donor_variant, intron_variant	Intron 5 of 40	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes AF: 0.000218 AC: 33 AN: 151694 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.0275

Gnomad AMR AF: 0.000263

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: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000211 AC: 26 AN: 123342 Hom.: 0 AF XY: 0.000225 AC XY: 15 AN XY: 66538

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000428

Gnomad OTH exome AF: 0.000783

GnomAD4 exome AF: 0.0000754 AC: 50 AN: 662720 Hom.: 0 Cov.: 9 AF XY: 0.0000716 AC XY: 25 AN XY: 349402

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000809

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000466

Gnomad4 OTH exome AF: 0.0000889

GnomAD4 genome AF: 0.000218 AC: 33 AN: 151694 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74080

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000263

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000287

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary sensory neuropathy-deafness-dementia syndrome Benign:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

May 08, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	16
DANN	Benign	0.59
Eigen	Benign	0.020
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.011	N
GERP RS		-0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.63
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: rs975957081; hg19: chr19-10290862;