rs193920894

Positions:

• chr17-49619281-A-C
• chr17-49619281-A-G
• chr17-49619281-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001007228.2(SPOP):​c.305T>G​(p.Phe102Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPOP NM_001007228.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: 9.32

Genes affected

SPOP (HGNC:11254): (speckle type BTB/POZ protein) This gene encodes a protein that may modulate the transcriptional repression activities of death-associated protein 6 (DAXX), which interacts with histone deacetylase, core histones, and other histone-associated proteins. In mouse, the encoded protein binds to the putative leucine zipper domain of macroH2A1.2, a variant H2A histone that is enriched on inactivated X chromosomes. The BTB/POZ domain of this protein has been shown in other proteins to mediate transcriptional repression and to interact with components of histone deacetylase co-repressor complexes. Alternative splicing of this gene results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest Required for nuclear localization (size 120) in uniprot entity SPOP_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001007228.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPOP. . Trascript score misZ 5.5316 (greater than threshold 3.09). GenCC has associacion of gene with neurodevelopmental disorder with microcephaly and dysmorphic facies.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPOP	NM_001007228.2	c.305T>G	p.Phe102Cys	missense_variant	4/10	ENST00000504102.6	NP_001007229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPOP	ENST00000504102.6	c.305T>G	p.Phe102Cys	missense_variant	4/10	1	NM_001007228.2	ENSP00000425905.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Malignant tumor of prostate Pathogenic:1 Uncertain:1

Likely pathogenic, no assertion criteria provided	research	Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, University of Tampere	-	- -
Uncertain significance, no assertion criteria provided	literature only	Science for Life laboratory, Karolinska Institutet	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;D;D;D;.;D;.;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;.;.;D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.042	D
MutationAssessor	Uncertain	2.8	M;M;M;M;.;.;.;.;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-7.1	D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.70
Sift	Benign	0.034	D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.082	T;T;T;T;.;D;.;.;.
Polyphen		1.0	D;D;D;D;.;.;.;.;.
Vest4		0.86
MutPred		0.73		Gain of methylation at K101 (P = 0.0283);Gain of methylation at K101 (P = 0.0283);Gain of methylation at K101 (P = 0.0283);Gain of methylation at K101 (P = 0.0283);Gain of methylation at K101 (P = 0.0283);Gain of methylation at K101 (P = 0.0283);Gain of methylation at K101 (P = 0.0283);Gain of methylation at K101 (P = 0.0283);Gain of methylation at K101 (P = 0.0283);
MVP		0.86
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.93
gMVP		0.99

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: rs193920894; hg19: chr17-47696643; COSMIC: COSV61652830; COSMIC: COSV61652830;