rs371674237

Variant names:

• chr17-49601950-C-G
• NM_001007228.2:c.895G>C

Your query was ambiguous. Multiple possible variants found:

• chr17-49601950-C-G
• chr17-49601950-C-T

Variant summary

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

The NM_001007228.2(SPOP):​c.895G>C​(p.Val299Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V299M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SPOP NM_001007228.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88

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.895G>C	p.Val299Leu	missense_variant	Exon 9 of 10	ENST00000504102.6	NP_001007229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPOP	ENST00000504102.6	c.895G>C	p.Val299Leu	missense_variant	Exon 9 of 10	1	NM_001007228.2	ENSP00000425905.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D;D;D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;D;.;.
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.7	M;M;M;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.48
Sift	Uncertain	0.027	D;D;D;D
Sift4G	Benign	0.063	T;T;T;T
Polyphen		0.034	B;B;B;B
Vest4		0.71
MutPred		0.41		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.77
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.64
gMVP		0.90

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: chr17-47679312;