17-49601872-T-C

Position:

• chr17-49601872-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001007228.2(SPOP):​c.973A>G​(p.Ile325Val) 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 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: 7.99

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
• 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=0.3826182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPOP	NM_001007228.2	c.973A>G	p.Ile325Val	missense_variant	9/10	ENST00000504102.6	NP_001007229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPOP	ENST00000504102.6	c.973A>G	p.Ile325Val	missense_variant	9/10	1	NM_001007228.2	ENSP00000425905	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;.;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.3	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.78	N;N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.017	D;D;D;D
Sift4G	Benign	0.24	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.59
MutPred		0.53		Gain of phosphorylation at Y327 (P = 0.1357);Gain of phosphorylation at Y327 (P = 0.1357);Gain of phosphorylation at Y327 (P = 0.1357);Gain of phosphorylation at Y327 (P = 0.1357);
MVP		0.69
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.39
gMVP		0.78

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

Other links and lift over

dbSNP: rs890324763; hg19: chr17-47679234; COSMIC: COSV61656037; COSMIC: COSV61656037;