17-49619069-C-G

Position:

• chr17-49619069-C-G

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.392G>C​(p.Trp131Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPOP NM_001007228.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.84

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 mutagenesis_site Strongly reduced affinity for substrate proteins. (size 0) in uniprot entity SPOP_HUMAN
• 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, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPOP	NM_001007228.2	c.392G>C	p.Trp131Ser	missense_variant	5/10	ENST00000504102.6	NP_001007229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPOP	ENST00000504102.6	c.392G>C	p.Trp131Ser	missense_variant	5/10	1	NM_001007228.2	ENSP00000425905.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Prostate adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;D;D;D;.;D;.;D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	.;D;.;.;T;T;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.018	D
MutationAssessor	Uncertain	2.6	M;M;M;M;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-11	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.62
Sift	Benign	0.033	D;D;D;D;D;D;D;D
Sift4G	Benign	0.18	T;T;T;T;.;T;.;.
Polyphen		1.0	D;D;D;D;.;.;.;.
Vest4		0.80
MutPred		0.66		Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);Gain of disorder (P = 0.002);
MVP		0.93
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
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: rs1057519969; hg19: chr17-47696431; COSMIC: COSV61653907; COSMIC: COSV61653907;