9-128822601-CAGTA-C

Variant names:

• chr9-128822601-CAGTA-C
• rs864309587
• NM_004435.2:c.889_892delAAGT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM4 BP6_Moderate BS1 BS2

The NM_004435.2(ENDOG):​c.889_892delAAGT​(p.Lys297GlufsTer6) variant causes a frameshift, stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00215 in 1,569,174 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0022 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (18 hom.)
• Consequence: ENDOG NM_004435.2 frameshift, stop_lost
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.15

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

Our verdict: Benign. The variant received -8 ACMG points.

• PM4: Stoplost variant in NM_004435.2 Downstream stopcodon found after 243 codons.
• BP6: Variant 9-128822601-CAGTA-C is Benign according to our data. Variant chr9-128822601-CAGTA-C is described in ClinVar as [Benign]. Clinvar id is 218639.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00214 (3039/1416940) while in subpopulation MID AF = 0.0233 (133/5704). AF 95% confidence interval is 0.0201. There are 18 homozygotes in GnomAdExome4. There are 1489 alleles in the male GnomAdExome4 subpopulation. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENDOG	NM_004435.2	c.889_892delAAGT	p.Lys297GlufsTer6	frameshift_variant, stop_lost	Exon 3 of 3	ENST00000372642.5	NP_004426.2
SPOUT1	NM_016390.4	c.*160_*163delTACT		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.889_892delAAGT	p.Lys297GlufsTer6	frameshift_variant, stop_lost	Exon 3 of 3	1	NM_004435.2	ENSP00000361725.4
SPOUT1	ENST00000361256	c.*160_*163delTACT		3_prime_UTR_variant	Exon 12 of 12	1	NM_016390.4	ENSP00000354812.5
ENSG00000286112	ENST00000651925	c.*2330_*2333delTACT		3_prime_UTR_variant	Exon 29 of 29			ENSP00000498386.1

Frequencies

GnomAD3 genomes AF: 0.00225 AC: 343 AN: 152116 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00865

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00243 AC: 436 AN: 179684 AF XY: 0.00228

Gnomad AFR exome AF: 0.000546

Gnomad AMR exome AF: 0.00677

Gnomad ASJ exome AF: 0.00368

Gnomad EAS exome AF: 0.00165

Gnomad FIN exome AF: 0.0000576

Gnomad NFE exome AF: 0.00220

Gnomad OTH exome AF: 0.00436

GnomAD4 exome AF: 0.00214 AC: 3039 AN: 1416940 Hom.: 18 AF XY: 0.00213 AC XY: 1489 AN XY: 700416

Gnomad4 AFR exome AF: 0.00100 AC: 33 AN: 32848

Gnomad4 AMR exome AF: 0.00714 AC: 264 AN: 36972

Gnomad4 ASJ exome AF: 0.00459 AC: 116 AN: 25258

Gnomad4 EAS exome AF: 0.00161 AC: 61 AN: 37918

Gnomad4 SAS exome AF: 0.000670 AC: 54 AN: 80538

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 49940

Gnomad4 NFE exome AF: 0.00204 AC: 2218 AN: 1089014

Gnomad4 Remaining exome AF: 0.00272 AC: 160 AN: 58748

GnomAD4 genome AF: 0.00225 AC: 342 AN: 152234 Hom.: 3 Cov.: 33 AF XY: 0.00238 AC XY: 177 AN XY: 74428

Gnomad4 AFR AF: 0.000818 AC: 0.000818331 AN: 0.000818331

Gnomad4 AMR AF: 0.00863 AC: 0.00863422 AN: 0.00863422

Gnomad4 ASJ AF: 0.00662 AC: 0.00662442 AN: 0.00662442

Gnomad4 EAS AF: 0.00135 AC: 0.0013524 AN: 0.0013524

Gnomad4 SAS AF: 0.000415 AC: 0.000414594 AN: 0.000414594

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00193 AC: 0.00192596 AN: 0.00192596

Gnomad4 OTH AF: 0.00331 AC: 0.00331126 AN: 0.00331126

Alfa AF: 0.000647 Hom.: 1

Bravo AF: 0.00253

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 17, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=86/114	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs864309587; hg19: chr9-131584880; COSMIC: COSV63510270; COSMIC: COSV63510270;