rs142647321

Variant names:

• chr19-10137146-A-C
• rs142647321
• NM_001130823.3:c.4428T>G

Your query was ambiguous. Multiple possible variants found:

• chr19-10137146-A-C
• chr19-10137146-A-G

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.4428T>G​(p.His1476Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0027 in 1,610,694 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1476N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (14 hom.)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.01
• Publications: 9 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 (MetaRNN=0.0046668053).
• BP6: Variant 19-10137146-A-C is Benign according to our data. Variant chr19-10137146-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 196998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 379 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.4428T>G	p.His1476Gln	missense	Exon 37 of 41	NP_001124295.1	P26358-2
	DNMT1	NM_001318730.2		c.4380T>G	p.His1460Gln	missense	Exon 36 of 40	NP_001305659.1
	DNMT1	NM_001379.4		c.4380T>G	p.His1460Gln	missense	Exon 36 of 40	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.4428T>G	p.His1476Gln	missense	Exon 37 of 41	ENSP00000352516.3	P26358-2
	DNMT1	ENST00000340748.8	TSL:1	c.4380T>G	p.His1460Gln	missense	Exon 36 of 40	ENSP00000345739.3	P26358-1
	DNMT1	ENST00000592705.5	TSL:1	n.*4118T>G		non_coding_transcript_exon	Exon 37 of 41	ENSP00000466657.1	K7EMU8

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 379 AN: 152156 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00326

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00245 AC: 592 AN: 241292 AF XY: 0.00242

Gnomad AFR exome AF: 0.000794

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.0218

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000981

Gnomad NFE exome AF: 0.00241

Gnomad OTH exome AF: 0.00274

GnomAD4 exome AF: 0.00272 AC: 3962 AN: 1458420 Hom.: 14 Cov.: 32 AF XY: 0.00267 AC XY: 1937 AN XY: 725248

African (AFR) AF: 0.000717 AC: 24 AN: 33452

American (AMR) AF: 0.00244 AC: 108 AN: 44278

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 548 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.000199 AC: 17 AN: 85568

European-Finnish (FIN) AF: 0.000114 AC: 6 AN: 52452

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5758

European-Non Finnish (NFE) AF: 0.00271 AC: 3016 AN: 1111098

Other (OTH) AF: 0.00375 AC: 226 AN: 60218

GnomAD4 genome AF: 0.00249 AC: 379 AN: 152274 Hom.: 1 Cov.: 32 AF XY: 0.00249 AC XY: 185 AN XY: 74446

African (AFR) AF: 0.000553 AC: 23 AN: 41566

American (AMR) AF: 0.00301 AC: 46 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00326 AC: 222 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00315 Hom.: 3

Bravo AF: 0.00245

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00210 AC: 255

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	2	Hereditary sensory neuropathy-deafness-dementia syndrome (2)
-	-	2	not specified (2)
-	-	1	DNMT1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.052
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.89	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		-1.0
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.25
Sift	Benign	0.051	T
Sift4G	Benign	0.12	T
Polyphen		0.046	B
Vest4		0.15
MutPred		0.37		Gain of solvent accessibility (P = 0.0338)
MVP		0.80
MPC		1.1
ClinPred		0.0095	T
GERP RS		-8.8
Varity_R		0.25
gMVP		0.88
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142647321; hg19: chr19-10247822; COSMIC: COSV106105258; COSMIC: COSV106105258;