Variant 17-49619062-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP3

The NM_001007228.2(SPOP):c.399C>G(p.Phe133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SPOP
NM_001007228.2 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.19

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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, 0.826

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPOP	NM_001007228.2 linkuse as main transcript	c.399C>G	p.Phe133Leu	missense_variant	5/10	ENST00000504102.6	NP_001007229.1	O43791

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPOP	ENST00000504102.6 linkuse as main transcript	c.399C>G	p.Phe133Leu	missense_variant	5/10	1	NM_001007228.2	ENSP00000425905.1		O43791

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

250984

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135636

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461862

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

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.:

Alfa

AF:

0.000111

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Malignant tumor of prostate

Uncertain:1

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

1.0

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

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

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.83

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

MetaSVM

Benign

-0.68

MutationAssessor

Pathogenic

3.0

M;M;M;M;.;.;.;.

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.1

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

REVEL

Uncertain

0.36

Sift

Benign

0.11

T;T;T;T;T;T;D;T

Sift4G

Benign

0.19

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

Polyphen

0.95

P;P;P;P;.;.;.;.

Vest4

0.79

MutPred

0.71

Loss of methylation at K134 (P = 0.0466);Loss of methylation at K134 (P = 0.0466);Loss of methylation at K134 (P = 0.0466);Loss of methylation at K134 (P = 0.0466);Loss of methylation at K134 (P = 0.0466);Loss of methylation at K134 (P = 0.0466);Loss of methylation at K134 (P = 0.0466);Loss of methylation at K134 (P = 0.0466);

MVP

0.77

ClinPred

0.97

GERP RS

4.3

Varity_R

0.83

gMVP

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over