17-49611316-C-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM5PP2PP3_StrongPP5_Moderate

The NM_001007228.2(SPOP):​c.622G>T​(p.Gly208Cys) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G208S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SPOP
NM_001007228.2 missense

Scores

11
6
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.91
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-49611316-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2574333.Status of the report is criteria_provided_single_submitter, 1 stars.
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.947
PP5
Variant 17-49611316-C-A is Pathogenic according to our data. Variant chr17-49611316-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3773986.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SPOPNM_001007228.2 linkc.622G>T p.Gly208Cys missense_variant Exon 6 of 10 ENST00000504102.6 NP_001007229.1 O43791

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SPOPENST00000504102.6 linkc.622G>T p.Gly208Cys missense_variant Exon 6 of 10 1 NM_001007228.2 ENSP00000425905.1 O43791

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Sep 20, 2024
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D;D;D;D;.;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.91
.;D;.;.;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.95
D;D;D;D;D;D
MetaSVM
Uncertain
0.65
D
MutationAssessor
Pathogenic
3.3
M;M;M;M;.;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-7.0
D;D;D;D;D;D
REVEL
Pathogenic
0.78
Sift
Benign
0.037
D;D;D;D;D;D
Sift4G
Uncertain
0.030
D;D;D;D;.;T
Polyphen
1.0
D;D;D;D;.;.
Vest4
0.70
MutPred
0.81
Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP
0.85
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.88
gMVP
0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-47688678; API