17-49619063-A-C

Position:

• chr17-49619063-A-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001007228.2(SPOP):​c.398T>G​(p.Phe133Cys) 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 Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F133I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPOP NM_001007228.2 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P: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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_001007228.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-49619063-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376547.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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, 0.913
• PP5: Variant 17-49619063-A-C is Pathogenic according to our data. Variant chr17-49619063-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376546.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOP	NM_001007228.2	c.398T>G	p.Phe133Cys	missense_variant	5/10	ENST00000504102.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOP	ENST00000504102.6	c.398T>G	p.Phe133Cys	missense_variant	5/10	1	NM_001007228.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;D;D;D;.;D;.;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	.;D;.;.;D;D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Pathogenic	3.0	M;M;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.8	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.019	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.030	D;D;D;D;.;D;.;.
Polyphen		1.0	D;D;D;D;.;.;.;.
Vest4		0.87
MutPred		0.77		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.70
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.88
gMVP		1.0

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: rs1057519967; hg19: chr17-47696425; COSMIC: COSV61653174; COSMIC: COSV61653174;