chr17-49619070-A-T

Variant names:

• chr17-49619070-A-T
• rs1057519968
• NM_001007228.2:c.391T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001007228.2(SPOP):​c.391T>A​(p.Trp131Arg) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W131G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPOP NM_001007228.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.24
• Publications: 61 publications found

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]

SPOP Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with microcephaly and dysmorphic facies

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Illumina
• neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies

  Inheritance: AD Classification: STRONG Submitted by: G2P

LOC107984999 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_001007228.2
• 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, neurodevelopmental disorder with relative macrocephaly and with or without cardiac or endocrine anomalies.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001007228.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPOP	NM_001007228.2	MANE Select	c.391T>A	p.Trp131Arg	missense	Exon 5 of 10	NP_001007229.1
	SPOP	NM_001007226.1		c.391T>A	p.Trp131Arg	missense	Exon 7 of 12	NP_001007227.1
	SPOP	NM_001007227.1		c.391T>A	p.Trp131Arg	missense	Exon 6 of 11	NP_001007228.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPOP	ENST00000504102.6	TSL:1 MANE Select	c.391T>A	p.Trp131Arg	missense	Exon 5 of 10	ENSP00000425905.1
	SPOP	ENST00000393328.6	TSL:1	c.391T>A	p.Trp131Arg	missense	Exon 6 of 11	ENSP00000377001.2
	SPOP	ENST00000347630.6	TSL:5	c.391T>A	p.Trp131Arg	missense	Exon 6 of 11	ENSP00000240327.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.71
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.68		Gain of disorder (P = 0.0052)
MVP		0.92
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057519968; hg19: chr17-47696432;