16-83118-C-G

Variant names:

• chr16-83118-C-G
• rs774617942
• NM_001015052.3:c.367C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001015052.3(MPG):​c.367C>G​(p.Leu123Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,612,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L123M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: MPG NM_001015052.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.496

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23891544).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MPG	NM_001015052.3	c.367C>G	p.Leu123Val	missense_variant	Exon 3 of 4	ENST00000356432.8	NP_001015052.1
MPG	NM_002434.4	c.382C>G	p.Leu128Val	missense_variant	Exon 4 of 5		NP_002425.2
MPG	NM_001015054.3	c.331C>G	p.Leu111Val	missense_variant	Exon 3 of 4		NP_001015054.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MPG	ENST00000356432.8	c.367C>G	p.Leu123Val	missense_variant	Exon 3 of 4	1	NM_001015052.3	ENSP00000348809.4
MPG	ENST00000219431.4	c.382C>G	p.Leu128Val	missense_variant	Exon 4 of 5	3		ENSP00000219431.4
MPG	ENST00000397817.5	c.331C>G	p.Leu111Val	missense_variant	Exon 3 of 4	2		ENSP00000380918.1
MPG	ENST00000436333.5	c.331C>G	p.Leu111Val	missense_variant	Exon 3 of 4	2		ENSP00000388097.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000279 AC: 7 AN: 250512 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135496

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1460788 Hom.: 0 Cov.: 32 AF XY: 0.0000592 AC XY: 43 AN XY: 726678

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000657

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152182 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.382C>G (p.L128V) alteration is located in exon 4 (coding exon 3) of the MPG gene. This alteration results from a C to G substitution at nucleotide position 382, causing the leucine (L) at amino acid position 128 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.28
DANN	Benign	0.96
DEOGEN2	Benign	0.016	T;.;.;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.26	N
LIST_S2	Uncertain	0.89	D;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.24	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	.;.;.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.6	D;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.051	T;T;D;T
Sift4G	Uncertain	0.050	T;T;T;T
Polyphen		0.13	B;.;.;B
Vest4		0.29, 0.29, 0.26
MutPred		0.53		.;.;.;Gain of disorder (P = 0.2407);
MVP		0.26
MPC		0.057
ClinPred		0.14	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.60

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

LitVar

Other links and lift over

dbSNP: rs774617942; hg19: chr16-133117;