17-49619063-A-G

Variant names:

• chr17-49619063-A-G
• rs1057519967
• NM_001007228.2:c.398T>C

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.398T>C​(p.Phe133Ser) 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. F133L) 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: 9.32
• Publications: 14 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

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• neurodevelopmental disorder with microcephaly and dysmorphic facies

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• 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, 16 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, 0.909

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPOP	NM_001007228.2	MANE Select	c.398T>C	p.Phe133Ser	missense	Exon 5 of 10	NP_001007229.1	O43791
	SPOP	NM_001007226.1		c.398T>C	p.Phe133Ser	missense	Exon 7 of 12	NP_001007227.1	O43791
	SPOP	NM_001007227.1		c.398T>C	p.Phe133Ser	missense	Exon 6 of 11	NP_001007228.1	O43791

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPOP	ENST00000504102.6	TSL:1 MANE Select	c.398T>C	p.Phe133Ser	missense	Exon 5 of 10	ENSP00000425905.1	O43791
	SPOP	ENST00000393328.6	TSL:1	c.398T>C	p.Phe133Ser	missense	Exon 6 of 11	ENSP00000377001.2	O43791
	SPOP	ENST00000347630.6	TSL:5	c.398T>C	p.Phe133Ser	missense	Exon 6 of 11	ENSP00000240327.2	O43791

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	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.050	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.76		Gain of disorder (P = 0.0205)
MVP		0.88
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.99

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

Other links and lift over

dbSNP: rs1057519967; hg19: chr17-47696425; COSMIC: COSV61653874; COSMIC: COSV61653874;