dbSNP rs1057519968: SPOP:p.Trp131Gly (chr17-49619070-A-C) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_001007228.2(SPOP):c.391T>G(p.Trp131Gly) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

SPOP
NM_001007228.2 missense

Scores

Clinical Significance

Other O:1

Conservation

PhyloP100: 9.24

Publications

61 publications found

Variant links:

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]

SPOP Gene-Disease associations (from GenCC):

neurodevelopmental disorder with microcephaly and dysmorphic facies
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies
Inheritance: AD Classification: STRONG Submitted by: G2P

SPOP links:

LOC107984999 (HGNC:):

LOC107984999 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_001007228.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the SPOP gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Trascript score misZ: 5.5316 (above the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with microcephaly and dysmorphic facies, neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPOP	NM_001007228.2 link	c.391T>G	p.Trp131Gly	missense_variant	Exon 5 of 10	ENST00000504102.6	NP_001007229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPOP	ENST00000504102.6 link	c.391T>G	p.Trp131Gly	missense_variant	Exon 5 of 10	1	NM_001007228.2	ENSP00000425905.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance:

Submissions summary: Other:1

Revision:

LINK: link

Submissions by phenotype

Neoplasm

Other:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.83

D;D;D;D;.;D;.;D

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.0

.;T;.;.;T;T;T;T

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.6

H;H;H;H;.;.;.;.

PhyloP100

9.2

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-10

D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0040

D;D;D;D;D;D;D;D

Sift4G

Benign

0.10

T;T;T;T;.;T;.;.

Vest4

0.85

ClinPred

1.0

GERP RS

5.4

Varity_R

0.96

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over