chr9-128822542-C-A

Variant names:

• chr9-128822542-C-A
• rs1830142918
• NM_004435.2:c.826C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004435.2(ENDOG):​c.826C>A​(p.Leu276Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,408,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ENDOG NM_004435.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40
• Publications: 0 publications found

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]

SPOUT1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

KYAT1 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004435.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENDOG	NM_004435.2	MANE Select	c.826C>A	p.Leu276Met	missense	Exon 3 of 3	NP_004426.2	Q14249
	SPOUT1	NM_016390.4	MANE Select	c.*223G>T		3_prime_UTR	Exon 12 of 12	NP_057474.2
	KYAT1-SPOUT1	NM_001414398.1		c.*223G>T		3_prime_UTR	Exon 23 of 23	NP_001401327.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENDOG	ENST00000372642.5	TSL:1 MANE Select	c.826C>A	p.Leu276Met	missense	Exon 3 of 3	ENSP00000361725.4	Q14249
	SPOUT1	ENST00000361256.10	TSL:1 MANE Select	c.*223G>T		3_prime_UTR	Exon 12 of 12	ENSP00000354812.5	Q5T280
	KYAT1	ENST00000651925.1		c.*2393G>T		3_prime_UTR	Exon 29 of 29	ENSP00000498386.1	A0A494C066

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.10e-7 AC: 1 AN: 1408008 Hom.: 0 Cov.: 31 AF XY: 0.00000144 AC XY: 1 AN XY: 695228

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32360

American (AMR) AF: 0.00 AC: 0 AN: 36166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25218

East Asian (EAS) AF: 0.00 AC: 0 AN: 37008

South Asian (SAS) AF: 0.00 AC: 0 AN: 79882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 9.23e-7 AC: 1 AN: 1083730

Other (OTH) AF: 0.00 AC: 0 AN: 58384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.84		Gain of catalytic residue at L276 (P = 0.0393)
MVP		0.76
MPC		1.0
ClinPred		0.93	D
GERP RS		3.7
Varity_R		0.23
gMVP		0.66
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs1830142918; hg19: chr9-131584821;