chr9-128822453-C-A

Variant names:

• chr9-128822453-C-A
• rs61737987
• NM_004435.2:c.737C>A

Variant summary

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

The NM_004435.2(ENDOG):​c.737C>A​(p.Thr246Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,431,884 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T246I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ENDOG NM_004435.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.31

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENDOG	NM_004435.2	c.737C>A	p.Thr246Asn	missense_variant	Exon 3 of 3	ENST00000372642.5	NP_004426.2
SPOUT1	NM_016390.4	c.*312G>T		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.737C>A	p.Thr246Asn	missense_variant	Exon 3 of 3	1	NM_004435.2	ENSP00000361725.4
SPOUT1	ENST00000361256	c.*312G>T		3_prime_UTR_variant	Exon 12 of 12	1	NM_016390.4	ENSP00000354812.5
ENSG00000286112	ENST00000651925	c.*2482G>T		3_prime_UTR_variant	Exon 29 of 29			ENSP00000498386.1
SPOUT1	ENST00000467582	c.*272G>T		3_prime_UTR_variant	Exon 3 of 3	2		ENSP00000473640.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1431884 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 709698

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: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.070
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.93	N
REVEL	Benign	0.20
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.017	D
Polyphen		0.24	B
Vest4		0.38
MutPred		0.63		Loss of glycosylation at T246 (P = 0.1014);
MVP		0.38
MPC		0.34
ClinPred		0.73	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs61737987; hg19: chr9-131584732;