4-52076820-G-A

Position:

• chr4-52076820-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_145263.4(SPATA18):​c.800G>A​(p.Arg267His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,614,056 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0058 (28 hom.)
• Consequence: SPATA18 NM_145263.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.857

Genes affected

SPATA18 (HGNC:29579): (spermatogenesis associated 18) This gene encodes a p53-inducible protein that is able to induce lysosome-like organelles within mitochondria that eliminate oxidized mitochondrial proteins, thereby contributing to mitochondrial quality control. Dysregulation of mitochondrial quality control is associated with cancer and degenerative diseases. The encoded protein mediates accumulation of the lysosome-like mitochondrial organelles through interaction with B cell lymphoma 2 interacting protein 3 and B cell lymphoma 2 interacting protein 3 like at the outer mitochondrial membrane, which allows translocation of lysosomal proteins to the mitochondrial matrix from the cytosol. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

SPATA18 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034707785).
• BP6: Variant 4-52076820-G-A is Benign according to our data. Variant chr4-52076820-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 788489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPATA18	NM_145263.4	c.800G>A	p.Arg267His	missense_variant	7/13	ENST00000295213.9	NP_660306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPATA18	ENST00000295213.9	c.800G>A	p.Arg267His	missense_variant	7/13	1	NM_145263.4	ENSP00000295213.4

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 582 AN: 152196 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00538

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00400 AC: 994 AN: 248752 Hom.: 5 AF XY: 0.00424 AC XY: 572 AN XY: 134774

Gnomad AFR exome AF: 0.000811

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00523

Gnomad NFE exome AF: 0.00533

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00578 AC: 8449 AN: 1461744 Hom.: 28 Cov.: 31 AF XY: 0.00574 AC XY: 4172 AN XY: 727168

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00219

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00150

Gnomad4 FIN exome AF: 0.00517

Gnomad4 NFE exome AF: 0.00656

Gnomad4 OTH exome AF: 0.00498

GnomAD4 genome AF: 0.00382 AC: 582 AN: 152312 Hom.: 1 Cov.: 31 AF XY: 0.00337 AC XY: 251 AN XY: 74484

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00452

Gnomad4 NFE AF: 0.00538

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00527 Hom.: 7

Bravo AF: 0.00392

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00363 AC: 441

EpiCase AF: 0.00556

EpiControl AF: 0.00504

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 28, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.6
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.012
Sift	Benign	0.27	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.022	B;B
Vest4		0.10
MVP		0.076
MPC		0.22
ClinPred		0.0060	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.28

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

Other links and lift over

dbSNP: rs139687172; hg19: chr4-52942986; COSMIC: COSV99039569; COSMIC: COSV99039569;