NM_004435.2:c.550C>G

Variant names:

• chr9-128820787-C-G
• NM_004435.2:c.550C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004435.2(ENDOG):​c.550C>G​(p.Arg184Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,248 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: 6.8e-7 (0 hom.)
• Consequence: ENDOG NM_004435.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73

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]

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]

ENSG00000286112 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENDOG	NM_004435.2	c.550C>G	p.Arg184Gly	missense_variant	Exon 2 of 3	ENST00000372642.5	NP_004426.2
SPOUT1	NM_016390.4	c.*1978G>C		3_prime_UTR_variant	Exon 12 of 12	ENST00000361256.10	NP_057474.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENDOG	ENST00000372642.5	c.550C>G	p.Arg184Gly	missense_variant	Exon 2 of 3	1	NM_004435.2	ENSP00000361725.4
SPOUT1	ENST00000361256	c.*1978G>C		3_prime_UTR_variant	Exon 12 of 12	1	NM_016390.4	ENSP00000354812.5
ENSG00000286112	ENST00000651925	c.*4148G>C		3_prime_UTR_variant	Exon 29 of 29			ENSP00000498386.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460248 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726220

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	4.3	H
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.88		Loss of MoRF binding (P = 0.0088);
MVP		0.93
MPC		1.1
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.92
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-131583066;