rs6504618

Variant names:

• chr17-49608827-A-G
• rs6504618
• NM_001007228.2:c.659-898T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001007228.2(SPOP):​c.659-898T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 152,016 control chromosomes in the GnomAD database, including 19,512 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (19512 hom., cov: 32)
• Consequence: SPOP NM_001007228.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.145
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPOP	NM_001007228.2	c.659-898T>C		intron_variant	Intron 6 of 9	ENST00000504102.6	NP_001007229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPOP	ENST00000504102.6	c.659-898T>C		intron_variant	Intron 6 of 9	1	NM_001007228.2	ENSP00000425905.1

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76209 AN: 151898 Hom.: 19457 Cov.: 32

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.468

Gnomad OTH AF: 0.465

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.502 AC: 76311 AN: 152016 Hom.: 19512 Cov.: 32 AF XY: 0.497 AC XY: 36948 AN XY: 74292

African (AFR) AF: 0.604 AC: 25039 AN: 41450

American (AMR) AF: 0.509 AC: 7770 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1188 AN: 3468

East Asian (EAS) AF: 0.434 AC: 2236 AN: 5158

South Asian (SAS) AF: 0.520 AC: 2504 AN: 4820

European-Finnish (FIN) AF: 0.407 AC: 4302 AN: 10570

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.468 AC: 31813 AN: 67956

Other (OTH) AF: 0.470 AC: 993 AN: 2112

Alfa AF: 0.471 Hom.: 33279

Bravo AF: 0.513

Asia WGS AF: 0.500 AC: 1741 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.7
DANN	Benign	0.33
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

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: rs6504618; hg19: chr17-47686189;