NM_001015052.3:c.697C>A

Variant names:

• chr16-85592-C-A
• rs1567126349
• NM_001015052.3:c.697C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001015052.3(MPG):​c.697C>A​(p.Gln233Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000959 in 1,459,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MPG NM_001015052.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.165
• Publications: 0 publications found

Genes affected

MPG (HGNC:7211): (N-methylpurine DNA glycosylase) Predicted to enable alkylbase DNA N-glycosylase activity. Predicted to be involved in base-excision repair. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NPRL3 (HGNC:14124): (NPR3 like, GATOR1 complex subunit) Contributes to GTPase activator activity. Involved in cellular response to amino acid starvation and negative regulation of TOR signaling. Located in lysosomal membrane. Part of GATOR1 complex. Implicated in focal epilepsy. [provided by Alliance of Genome Resources, Apr 2022]

NPRL3 Gene-Disease associations (from GenCC):

• focal epilepsy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, familial focal, with variable foci 3

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial focal epilepsy with variable foci

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04661256).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001015052.3. 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
	MPG	NM_001015052.3	MANE Select	c.697C>A	p.Gln233Lys	missense	Exon 4 of 4	NP_001015052.1	P29372-4
	NPRL3	NM_001077350.3	MANE Select	c.*1113G>T		3_prime_UTR	Exon 14 of 14	NP_001070818.1	Q12980
	MPG	NM_002434.4		c.712C>A	p.Gln238Lys	missense	Exon 5 of 5	NP_002425.2	Q1W6H1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MPG	ENST00000356432.8	TSL:1 MANE Select	c.697C>A	p.Gln233Lys	missense	Exon 4 of 4	ENSP00000348809.4	P29372-4
	NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.*1113G>T		3_prime_UTR	Exon 14 of 14	ENSP00000478273.1	Q12980
	MPG	ENST00000219431.4	TSL:3	c.712C>A	p.Gln238Lys	missense	Exon 5 of 5	ENSP00000219431.4	P29372-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248318 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000959 AC: 14 AN: 1459856 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726012

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.0000224 AC: 1 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111008

Other (OTH) AF: 0.0000166 AC: 1 AN: 60306

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.26
DANN	Benign	0.52
DEOGEN2	Benign	0.010	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.14	N
PhyloP100		-0.17
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.024
Sift	Benign	0.65	T
Sift4G	Benign	0.96	T
Polyphen		0.0	B
Vest4		0.086
MutPred		0.41		Gain of ubiquitination at Q238 (P = 0.0104)
MVP		0.27
MPC		0.064
ClinPred		0.014	T
GERP RS		0.47
Varity_R		0.14
gMVP		0.50
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1567126349; hg19: chr16-135591;