9-128822501-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004435.2(ENDOG):c.785G>A(p.Arg262His) variant causes a missense change. The variant allele was found at a frequency of 0.0000237 in 1,561,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ENDOG
NM_004435.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.37

Variant links:

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]

ENDOG links:

SPOUT1 (HGNC:26933): (SPOUT domain containing methyltransferase 1) Enables miRNA binding activity. Involved in maintenance of centrosome location and production of miRNAs involved in gene silencing by miRNA. Located in kinetochore; mitotic spindle; and spindle pole centrosome. [provided by Alliance of Genome Resources, Apr 2022]

SPOUT1 links:

ENSG00000286112 (HGNC:):

ENSG00000286112 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.22651815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENDOG	NM_004435.2 link	c.785G>A	p.Arg262His	missense_variant	Exon 3 of 3	ENST00000372642.5	NP_004426.2	Q14249E5KNL5
SPOUT1	NM_016390.4 link	c.*264C>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000361256.10	NP_057474.2	Q5T280

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENDOG	ENST00000372642.5 link	c.785G>A	p.Arg262His	missense_variant	Exon 3 of 3	1	NM_004435.2	ENSP00000361725.4	Q14249
SPOUT1	ENST00000361256 link	c.*264C>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_016390.4	ENSP00000354812.5	Q5T280
ENSG00000286112	ENST00000651925 link	c.*2434C>T		3_prime_UTR_variant	Exon 29 of 29			ENSP00000498386.1	A0A494C066
SPOUT1	ENST00000467582 link	c.*224C>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000473640.1	R4GNG4

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000601

AC:

AN:

166418

Hom.:

AF XY:

0.0000567

AC XY:

AN XY:

88168

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.000496

Gnomad NFE exome

AF:

0.0000304

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000213

AC:

AN:

1409542

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

696142

show subpopulations

Gnomad4 AFR exome

AF:

0.0000310

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:

0.000421

Gnomad4 NFE exome

AF:

0.00000645

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000847

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000254

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.785G>A (p.R262H) alteration is located in exon 3 (coding exon 3) of the ENDOG gene. This alteration results from a G to A substitution at nucleotide position 785, causing the arginine (R) at amino acid position 262 to be replaced by a histidine (H). 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

0.14

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-0.097

Eigen_PC

Benign

0.073

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.032

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.3

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.74

REVEL

Benign

0.10

Sift

Benign

0.14

Sift4G

Benign

0.16

Polyphen

0.014

Vest4

0.15

MVP

0.74

MPC

0.38

ClinPred

0.13

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.098

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over