rs139106189

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PVS1_StrongBP6

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 Conflicting classifications of pathogenicity (no stars).

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 7.48

Publications

6 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

Neu-Laxova syndrome 1
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
PSPH deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
neurometabolic disorder due to serine deficiency
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

PSPH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.19911504 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 403351.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSPH	NM_004577.4 link	c.275+1delG		splice_donor_variant, intron_variant	Intron 5 of 7	ENST00000275605.8	NP_004568.2	P78330A0A024RDL3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSPH	ENST00000275605.8 link	c.275+1delG		splice_donor_variant, intron_variant	Intron 5 of 7	1	NM_004577.4	ENSP00000275605.3		P78330

Frequencies

GnomAD3 genomes

AF:

0.242

AC:

31704

AN:

131022

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0000375

AC:

AN:

239758

AF XY:

0.0000386

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000588

Gnomad FIN exome

AF:

0.0000473

Gnomad NFE exome

AF:

0.0000360

Gnomad OTH exome

AF:

0.000170

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0280

AC:

32869

AN:

1174690

Hom.:

Cov.:

AF XY:

0.0296

AC XY:

17130

AN XY:

579328

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.246

AC:

3984

AN:

16206

American (AMR)

AF:

0.0506

AC:

1553

AN:

30688

Ashkenazi Jewish (ASJ)

AF:

0.0260

AC:

552

AN:

21242

East Asian (EAS)

AF:

0.288

AC:

6806

AN:

23618

South Asian (SAS)

AF:

0.0570

AC:

3002

AN:

52702

European-Finnish (FIN)

AF:

0.0782

AC:

3123

AN:

39954

Middle Eastern (MID)

AF:

0.0707

AC:

297

AN:

4202

European-Non Finnish (NFE)

AF:

0.0123

AC:

11558

AN:

939542

Other (OTH)

AF:

0.0428

AC:

1994

AN:

46536

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.263

Heterozygous variant carriers

3760

7519

11279

15038

18798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.242

AC:

31750

AN:

131120

Hom.:

Cov.:

AF XY:

0.246

AC XY:

15726

AN XY:

63940

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.469

AC:

16749

AN:

35682

American (AMR)

AF:

0.222

AC:

2768

AN:

12484

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

358

AN:

3106

East Asian (EAS)

AF:

0.401

AC:

1629

AN:

4060

South Asian (SAS)

AF:

0.292

AC:

1099

AN:

3758

European-Finnish (FIN)

AF:

0.179

AC:

1632

AN:

9142

Middle Eastern (MID)

AF:

0.147

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.117

AC:

7044

AN:

60064

Other (OTH)

AF:

0.220

AC:

389

AN:

1772

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.317

Heterozygous variant carriers

1705

3411

5116

6822

8527

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.151

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Neurometabolic disorder due to serine deficiency

Uncertain:1

Aug 22, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:1

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.5

Mutation Taster

=16/84

disease causing

(source)

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

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rs139106189

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over