chr9-128818808-G-A

Variant names:

• chr9-128818808-G-A
• rs1327013077
• NM_004435.2:c.124G>A

Variant summary

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

The NM_004435.2(ENDOG):​c.124G>A​(p.Val42Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000939 in 1,278,350 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000080 (0 hom.)
• Consequence: ENDOG NM_004435.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.510

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1670847).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENDOG	NM_004435.2	c.124G>A	p.Val42Met	missense_variant	Exon 1 of 3	ENST00000372642.5	NP_004426.2
ENDOG	XM_011518347.3	c.124G>A	p.Val42Met	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.124G>A	p.Val42Met	missense_variant	Exon 1 of 3	1	NM_004435.2	ENSP00000361725.4

Frequencies

GnomAD3 genomes AF: 0.0000199 AC: 3 AN: 150678 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000485

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000798 AC: 9 AN: 1127672 Hom.: 0 Cov.: 33 AF XY: 0.00000185 AC XY: 1 AN XY: 540508

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: 0.00000952

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000199 AC: 3 AN: 150678 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73498

Gnomad4 AFR AF: 0.0000485

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: 0.0000148

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.056
Sift	Benign	0.23	T
Sift4G	Benign	0.26	T
Polyphen		0.63	P
Vest4		0.088
MutPred		0.29		Gain of MoRF binding (P = 0.1045);
MVP		0.44
MPC		0.30
ClinPred		0.17	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.037
gMVP		0.40

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: rs1327013077; hg19: chr9-131581087;