17-49611348-G-C

Variant names:

• chr17-49611348-G-C
• NM_001007228.2:c.590C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001007228.2(SPOP):​c.590C>G​(p.Ser197Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SPOP NM_001007228.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SPOP gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Trascript score misZ: 5.5316 (above the threshold of 3.09). GenCC associations: The gene is linked to neurodevelopmental disorder with microcephaly and dysmorphic facies.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPOP	NM_001007228.2	c.590C>G	p.Ser197Cys	missense_variant	Exon 6 of 10	ENST00000504102.6	NP_001007229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPOP	ENST00000504102.6	c.590C>G	p.Ser197Cys	missense_variant	Exon 6 of 10	1	NM_001007228.2	ENSP00000425905.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461878 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 31, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;D;D;D;.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	.;T;.;.;T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	2.0	M;M;M;M;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	D;D;D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.035	D;D;D;D;.;D
Polyphen		0.99	D;D;D;D;.;.
Vest4		0.53
MutPred		0.35		Loss of catalytic residue at S197 (P = 0.0459);Loss of catalytic residue at S197 (P = 0.0459);Loss of catalytic residue at S197 (P = 0.0459);Loss of catalytic residue at S197 (P = 0.0459);Loss of catalytic residue at S197 (P = 0.0459);Loss of catalytic residue at S197 (P = 0.0459);
MVP		0.72
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.63
gMVP		0.81

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: chr17-47688710;