4-52077011-G-T

Position:

• chr4-52077011-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_145263.4(SPATA18):​c.991G>T​(p.Val331Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPATA18 NM_145263.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.47

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPATA18	NM_145263.4	c.991G>T	p.Val331Phe	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.991G>T	p.Val331Phe	missense_variant	7/13	1	NM_145263.4	ENSP00000295213.4
SPATA18	ENST00000419395.6	c.895G>T	p.Val299Phe	missense_variant	6/12	2		ENSP00000415309.2
SPATA18	ENST00000505320.5	n.991G>T		non_coding_transcript_exon_variant	7/13	5		ENSP00000421204.1
SPATA18	ENST00000511028.1	n.1277G>T		non_coding_transcript_exon_variant	7/10	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724300

Gnomad4 AFR exome AF: 0.0000899

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.7	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.019	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.54		Loss of catalytic residue at Q332 (P = 0.0955);.;
MVP		0.43
MPC		0.77
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.60
gMVP		0.75

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: rs193921037; hg19: chr4-52943177;