17-49600402-TG-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001007228.2(SPOP):c.1100del(p.Pro367HisfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P367P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPOP NM_001007228.2 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.97

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOP	NM_001007228.2	c.1100del	p.Pro367HisfsTer5	frameshift_variant	10/10	ENST00000504102.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOP	ENST00000504102.6	c.1100del	p.Pro367HisfsTer5	frameshift_variant	10/10	1	NM_001007228.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodevelopmental disorder with microcephaly and dysmorphic facies Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Apr 12, 2024

The SPOP c.1100del (p.Pro367Hisfs*5) variant, to our knowledge, has not been reported in the medical literature and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a frameshift by deleting a single nucleotide, leading to a premature termination codon; however, because this occurs in the last exon and is only predicted to delete eight amino acids, this is not predicted to lead to nonsense mediated decay. One publication indicates a nuclear localization signal may be located in the amino acids that would be deleted due to this variation (Shi Q et al., PMID: 31771591), but another publication indicates the nuclear localization signal is in another region (Nagai Y et al., PMID: 9414087). Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time. -

Computational scores

Source: dbNSFP v4.3

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: chr17-47677764;