chr16-85673-G-A

Variant names:

• chr16-85673-G-A
• rs974375687
• NM_001015052.3:c.778G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001015052.3(MPG):​c.778G>A​(p.Gly260Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000148 in 1,423,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 0.000015 (0 hom.)
• Consequence: MPG NM_001015052.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91
• Publications: 14 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19143692).

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.778G>A	p.Gly260Ser	missense	Exon 4 of 4	NP_001015052.1	P29372-4
	NPRL3	NM_001077350.3	MANE Select	c.*1032C>T		3_prime_UTR	Exon 14 of 14	NP_001070818.1	Q12980
	MPG	NM_002434.4		c.793G>A	p.Gly265Ser	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.778G>A	p.Gly260Ser	missense	Exon 4 of 4	ENSP00000348809.4	P29372-4
	NPRL3	ENST00000611875.5	TSL:5 MANE Select	c.*1032C>T		3_prime_UTR	Exon 14 of 14	ENSP00000478273.1	Q12980
	MPG	ENST00000219431.4	TSL:3	c.793G>A	p.Gly265Ser	missense	Exon 5 of 5	ENSP00000219431.4	P29372-1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000137 AC: 3 AN: 218648 AF XY: 0.0000169

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000305

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000148 AC: 21 AN: 1423138 Hom.: 0 Cov.: 31 AF XY: 0.0000128 AC XY: 9 AN XY: 702626

African (AFR) AF: 0.0000307 AC: 1 AN: 32600

American (AMR) AF: 0.00 AC: 0 AN: 41314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24206

East Asian (EAS) AF: 0.00 AC: 0 AN: 39084

South Asian (SAS) AF: 0.00 AC: 0 AN: 81868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 0.0000174 AC: 19 AN: 1088886

Other (OTH) AF: 0.0000171 AC: 1 AN: 58500

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.089
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.035	N
PhyloP100		4.9
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.071
Sift	Benign	0.12	T
Sift4G	Benign	0.25	T
Polyphen		0.18	B
Vest4		0.10
MutPred		0.47		Gain of glycosylation at G265 (P = 0.0549)
MVP		0.42
MPC		0.062
ClinPred		0.18	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.25
gMVP		0.43
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs974375687; hg19: chr16-135672; COSMIC: COSV104985849; COSMIC: COSV104985849;