19-10173163-G-T

Variant names:

• chr19-10173163-G-T
• NM_001130823.3:c.695C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001130823.3(DNMT1):​c.695C>A​(p.Pro232Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNMT1 NM_001130823.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.367

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.059997916).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNMT1	NM_001130823.3	c.695C>A	p.Pro232Gln	missense_variant	Exon 9 of 41	ENST00000359526.9	NP_001124295.1
DNMT1	NM_001318730.2	c.647C>A	p.Pro216Gln	missense_variant	Exon 8 of 40		NP_001305659.1
DNMT1	NM_001379.4	c.647C>A	p.Pro216Gln	missense_variant	Exon 8 of 40		NP_001370.1
DNMT1	NM_001318731.2	c.332C>A	p.Pro111Gln	missense_variant	Exon 9 of 41		NP_001305660.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNMT1	ENST00000359526.9	c.695C>A	p.Pro232Gln	missense_variant	Exon 9 of 41	1	NM_001130823.3	ENSP00000352516.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.9
DANN	Benign	0.88
DEOGEN2	Benign	0.40	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.52	N;N;.
REVEL	Benign	0.011
Sift	Benign	0.059	T;T;.
Sift4G	Benign	0.61	T;T;T
Polyphen		0.34	B;P;.
Vest4		0.29
MutPred		0.21		Gain of helix (P = 0.0199);.;.;
MVP		0.35
MPC		0.38
ClinPred		0.080	T
GERP RS		0.031
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.026
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-10283839; COSMIC: COSV61578601; COSMIC: COSV61578601;