17-49611390-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001007228.2(SPOP):c.548A>C(p.Glu183Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPOP NM_001007228.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 5 ACMG points.

• PM1: In a region_of_interest Required for nuclear localization (size 120) in uniprot entity SPOP_HUMAN there are 28 pathogenic changes around while only 0 benign (100%) in NM_001007228.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SPOP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPOP	NM_001007228.2	c.548A>C	p.Glu183Ala	missense_variant	6/10	ENST00000504102.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPOP	ENST00000504102.6	c.548A>C	p.Glu183Ala	missense_variant	6/10	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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Jun 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;D;D;D;.;T;.
Eigen	Benign	0.086
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.4	L;L;L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.027	D;D;D;D;D;D;D
Sift4G	Benign	0.29	T;T;T;T;.;T;.
Polyphen		0.20	B;B;B;B;.;.;.
Vest4		0.39
MutPred		0.42		Gain of ubiquitination at K180 (P = 0.115);Gain of ubiquitination at K180 (P = 0.115);Gain of ubiquitination at K180 (P = 0.115);Gain of ubiquitination at K180 (P = 0.115);Gain of ubiquitination at K180 (P = 0.115);Gain of ubiquitination at K180 (P = 0.115);Gain of ubiquitination at K180 (P = 0.115);
MVP		0.69
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.47
gMVP		0.67

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: chr17-47688752;