4-52076895-A-G

Position:

• chr4-52076895-A-G

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.875A>G​(p.Lys292Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,614,198 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (8 hom., cov: 31)
  • Exomes 𝑓: 0.012 (123 hom.)
• Consequence: SPATA18 NM_145263.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.50

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=0.0032060742).
• BP6: Variant 4-52076895-A-G is Benign according to our data. Variant chr4-52076895-A-G is described in ClinVar as [Benign]. Clinvar id is 710427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPATA18	NM_145263.4	c.875A>G	p.Lys292Arg	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.875A>G	p.Lys292Arg	missense_variant	7/13	1	NM_145263.4	ENSP00000295213.4

Frequencies

GnomAD3 genomes AF: 0.00796 AC: 1212 AN: 152194 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00720

Gnomad ASJ AF: 0.00865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0136

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00752 AC: 1888 AN: 251100 Hom.: 14 AF XY: 0.00732 AC XY: 994 AN XY: 135736

Gnomad AFR exome AF: 0.00203

Gnomad AMR exome AF: 0.00393

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.0133

Gnomad OTH exome AF: 0.00749

GnomAD4 exome AF: 0.0122 AC: 17851 AN: 1461886 Hom.: 123 Cov.: 31 AF XY: 0.0118 AC XY: 8582 AN XY: 727248

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.00182

Gnomad4 NFE exome AF: 0.0150

Gnomad4 OTH exome AF: 0.00841

GnomAD4 genome AF: 0.00796 AC: 1212 AN: 152312 Hom.: 8 Cov.: 31 AF XY: 0.00741 AC XY: 552 AN XY: 74484

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00719

Gnomad4 ASJ AF: 0.00865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.0136

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.0124 Hom.: 22

Bravo AF: 0.00782

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0156 AC: 60

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0121 AC: 104

ExAC AF: 0.00718 AC: 872

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0132

EpiControl AF: 0.0123

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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	0.072
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.034	T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.60	T;T
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.045
Sift	Benign	0.38	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0040	B;B
Vest4		0.043
MVP		0.048
MPC		0.13
ClinPred		0.0038	T
GERP RS		0.38
Varity_R		0.051
gMVP		0.20

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: rs141695566; hg19: chr4-52943061;