chr17-49619281-A-T

Position:

• chr17-49619281-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_001007228.2(SPOP):​c.305T>A​(p.Phe102Tyr) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPOP NM_001007228.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Required for nuclear localization (size 120) in uniprot entity SPOP_HUMAN there are 5 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 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.789

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPOP	NM_001007228.2	c.305T>A	p.Phe102Tyr	missense_variant	4/10	ENST00000504102.6	NP_001007229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPOP	ENST00000504102.6	c.305T>A	p.Phe102Tyr	missense_variant	4/10	1	NM_001007228.2	ENSP00000425905.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;D;D;D;.;T;.;T;.
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;.;.;D;D;D;D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.1	M;M;M;M;.;.;.;.;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Uncertain	-2.5	N;N;N;N;N;D;D;D;D
REVEL	Uncertain	0.41
Sift	Benign	0.058	T;T;T;T;T;T;D;T;T
Sift4G	Benign	0.22	T;T;T;T;.;T;.;.;.
Polyphen		1.0	D;D;D;D;.;.;.;.;.
Vest4		0.69
MutPred		0.66		Loss of methylation at K103 (P = 0.0281);Loss of methylation at K103 (P = 0.0281);Loss of methylation at K103 (P = 0.0281);Loss of methylation at K103 (P = 0.0281);Loss of methylation at K103 (P = 0.0281);Loss of methylation at K103 (P = 0.0281);Loss of methylation at K103 (P = 0.0281);Loss of methylation at K103 (P = 0.0281);Loss of methylation at K103 (P = 0.0281);
MVP		0.69
ClinPred		0.91	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.71
gMVP		0.92

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: chr17-47696643; COSMIC: COSV61654088; COSMIC: COSV61654088;