17-49611326-C-A

Position:

• chr17-49611326-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001007228.2(SPOP):​c.612G>T​(p.Leu204Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPOP NM_001007228.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115

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 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.252809).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPOP	NM_001007228.2	c.612G>T	p.Leu204Phe	missense_variant	6/10	ENST00000504102.6	NP_001007229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPOP	ENST00000504102.6	c.612G>T	p.Leu204Phe	missense_variant	6/10	1	NM_001007228.2	ENSP00000425905	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Uncertain	0.46	T;T;T;T;.;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.74	.;T;.;.;T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.25	T;T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.070	N;N;N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.0	N;N;N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.22	T;T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;.;T
Polyphen		0.068	B;B;B;B;.;.
Vest4		0.43
MutPred		0.58		Loss of catalytic residue at L204 (P = 0.2144);Loss of catalytic residue at L204 (P = 0.2144);Loss of catalytic residue at L204 (P = 0.2144);Loss of catalytic residue at L204 (P = 0.2144);Loss of catalytic residue at L204 (P = 0.2144);Loss of catalytic residue at L204 (P = 0.2144);
MVP		0.86
ClinPred		0.75	D
GERP RS		4.5
Varity_R		0.34
gMVP		0.85

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: chr17-47688688;