4-52072099-G-A

Position:

• chr4-52072099-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.701G>A​(p.Arg234Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00354 in 1,614,012 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (16 hom.)
• Consequence: SPATA18 NM_145263.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.260

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=0.005424261).
• BP6: Variant 4-52072099-G-A is Benign according to our data. Variant chr4-52072099-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 714198.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPATA18	NM_145263.4	c.701G>A	p.Arg234Gln	missense_variant	6/13	ENST00000295213.9	NP_660306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPATA18	ENST00000295213.9	c.701G>A	p.Arg234Gln	missense_variant	6/13	1	NM_145263.4	ENSP00000295213.4

Frequencies

GnomAD3 genomes AF: 0.00205 AC: 311 AN: 152020 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000894

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000777

Gnomad SAS AF: 0.000831

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00359

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00211 AC: 531 AN: 251226 Hom.: 0 AF XY: 0.00218 AC XY: 296 AN XY: 135788

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00190

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00349

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00369 AC: 5395 AN: 1461874 Hom.: 16 Cov.: 34 AF XY: 0.00347 AC XY: 2527 AN XY: 727236

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00108

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.000374

Gnomad4 NFE exome AF: 0.00447

Gnomad4 OTH exome AF: 0.00338

GnomAD4 genome AF: 0.00204 AC: 311 AN: 152138 Hom.: 1 Cov.: 32 AF XY: 0.00190 AC XY: 141 AN XY: 74366

Gnomad4 AFR AF: 0.000891

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000779

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00359

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00367 Hom.: 1

Bravo AF: 0.00250

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00213 AC: 258

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00367

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 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.1
DANN	Benign	0.83
DEOGEN2	Benign	0.045	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.053
Sift	Benign	0.19	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.028	B;B
Vest4		0.062
MVP		0.17
MPC		0.18
ClinPred		0.0028	T
GERP RS		0.30
Varity_R		0.037
gMVP		0.14

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: rs139201868; hg19: chr4-52938265; COSMIC: COSV54641802; COSMIC: COSV54641802;