rs138998574

Variant names:

• chr19-10180179-G-A
• rs138998574
• NM_001130823.3:c.493+8C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-10180179-G-A
• chr19-10180179-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001130823.3(DNMT1):​c.493+8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 768,956 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: DNMT1 NM_001130823.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001940
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.42
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 19-10180179-G-A is Benign according to our data. Variant chr19-10180179-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 161 Unknown,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.493+8C>T		splice_region intron	N/A	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.445+171C>T		intron	N/A	NP_001305659.1
	DNMT1	NM_001379.4		c.445+171C>T		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.493+8C>T		splice_region intron	N/A	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.445+171C>T		intron	N/A	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000590619.1	TSL:1	c.79+8C>T		splice_region intron	N/A	ENSP00000468062.1	K7ER10

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 151682 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00207

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00105 AC: 122 AN: 116636 AF XY: 0.00108

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000669

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000436

Gnomad NFE exome AF: 0.00173

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.00134 AC: 824 AN: 617156 Hom.: 1 Cov.: 8 AF XY: 0.00133 AC XY: 433 AN XY: 326402

African (AFR) AF: 0.000120 AC: 2 AN: 16722

American (AMR) AF: 0.000748 AC: 24 AN: 32086

Ashkenazi Jewish (ASJ) AF: 0.00117 AC: 22 AN: 18798

East Asian (EAS) AF: 0.00 AC: 0 AN: 31546

South Asian (SAS) AF: 0.000852 AC: 51 AN: 59826

European-Finnish (FIN) AF: 0.000255 AC: 8 AN: 31420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2506

European-Non Finnish (NFE) AF: 0.00176 AC: 690 AN: 392214

Other (OTH) AF: 0.000843 AC: 27 AN: 32038

GnomAD4 genome AF: 0.00106 AC: 161 AN: 151800 Hom.: 0 Cov.: 31 AF XY: 0.000863 AC XY: 64 AN XY: 74178

African (AFR) AF: 0.000193 AC: 8 AN: 41364

American (AMR) AF: 0.000395 AC: 6 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00207 AC: 141 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.000986

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	2	Hereditary sensory neuropathy-deafness-dementia syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.2
DANN	Benign	0.29
PhyloP100		1.4
PromoterAI		0.015	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.054
SpliceAI score (max)		0.060		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: rs138998574; hg19: chr19-10290855;