NM_004435.2:c.352G>C

Variant names:

• chr9-128819036-G-C
• rs768753770
• NM_004435.2:c.352G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004435.2(ENDOG):​c.352G>C​(p.Asp118His) variant causes a missense change. The variant allele was found at a frequency of 0.00000297 in 1,345,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: ENDOG NM_004435.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.75

Genes affected

ENDOG (HGNC:3346): (endonuclease G) The protein encoded by this gene is a nuclear encoded endonuclease that is localized in the mitochondrion. The encoded protein is widely distributed among animals and cleaves DNA at GC tracts. This protein is capable of generating the RNA primers required by DNA polymerase gamma to initiate replication of mitochondrial DNA. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENDOG	NM_004435.2	c.352G>C	p.Asp118His	missense_variant	Exon 1 of 3	ENST00000372642.5	NP_004426.2
ENDOG	XM_011518347.3	c.352G>C	p.Asp118His	missense_variant	Exon 1 of 4		XP_011516649.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENDOG	ENST00000372642.5	c.352G>C	p.Asp118His	missense_variant	Exon 1 of 3	1	NM_004435.2	ENSP00000361725.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000297 AC: 4 AN: 1345880 Hom.: 0 Cov.: 33 AF XY: 0.00000452 AC XY: 3 AN XY: 663092

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: 0.0000534

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000979 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	4.3	H
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.67
MutPred		0.79		Gain of catalytic residue at R116 (P = 0.085);
MVP		0.86
MPC		1.1
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.92
gMVP		0.89

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: rs768753770; hg19: chr9-131581315;