rs139106189

Positions:

• chr7-56019598-AC-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PVS1_Strong BP6_Moderate

The NM_004577.4(PSPH):​c.275+1delG variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (0 hom., cov: 0)
  • Exomes 𝑓: 0.028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSPH NM_004577.4 splice_donor, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 7.48

Genes affected

PSPH (HGNC:9577): (phosphoserine phosphatase) The protein encoded by this gene belongs to a subfamily of the phosphotransferases. This encoded enzyme is responsible for the third and last step in L-serine formation. It catalyzes magnesium-dependent hydrolysis of L-phosphoserine and is also involved in an exchange reaction between L-serine and L-phosphoserine. Deficiency of this protein is thought to be linked to Williams syndrome. [provided by RefSeq, Jul 2008]

PSPH (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.19764012 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.2, offset of 0 (no position change), new splice context is: taaGTaaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 7-56019598-AC-A is Benign according to our data. Variant chr7-56019598-AC-A is described in ClinVar as [Likely_benign]. Clinvar id is 403351.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-56019598-AC-A is described in Lovd as [Benign]. Variant chr7-56019598-AC-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSPH	NM_004577.4	c.275+1delG		splice_donor_variant, intron_variant		ENST00000275605.8	NP_004568.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSPH	ENST00000275605.8	c.275+1delG		splice_donor_variant, intron_variant		1	NM_004577.4	ENSP00000275605.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 31704 AN: 131022 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.0600

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.151

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.219

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0280 AC: 32869 AN: 1174690 Hom.: 0 Cov.: 30 AF XY: 0.0296 AC XY: 17130 AN XY: 579328

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.0506

Gnomad4 ASJ exome AF: 0.0260

Gnomad4 EAS exome AF: 0.288

Gnomad4 SAS exome AF: 0.0570

Gnomad4 FIN exome AF: 0.0782

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.0428

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.242 AC: 31750 AN: 131120 Hom.: 0 Cov.: 0 AF XY: 0.246 AC XY: 15726 AN XY: 63940

Gnomad4 AFR AF: 0.469

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.115

Gnomad4 EAS AF: 0.401

Gnomad4 SAS AF: 0.292

Gnomad4 FIN AF: 0.179

Gnomad4 NFE AF: 0.117

Gnomad4 OTH AF: 0.220

Alfa AF: 0.151 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene has been reported in 3-phosphoserine phosphatase deficiency and developmental delay. Limited evidence for role in disease an LOF variants. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs139106189; hg19: chr7-56087291;