rs139106189

Variant names:

• chr7-56019598-AC-A
• rs139106189
• NM_004577.4:c.275+1delG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PVS1_Strong BP6

The ENST00000275605.8(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 ENST00000275605.8 splice_donor, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.48
• Publications: 6 publications found

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

ACMG classification

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 VariationId is 403351.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000275605.8. 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
	PSPH	NM_004577.4	MANE Select	c.275+1delG		splice_donor intron	N/A	NP_004568.2
	PSPH	NM_001370503.1		c.275+1delG		splice_donor intron	N/A	NP_001357432.1
	PSPH	NM_001370504.1		c.275+1delG		splice_donor intron	N/A	NP_001357433.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSPH	ENST00000275605.8	TSL:1 MANE Select	c.275+1delG		splice_donor intron	N/A	ENSP00000275605.3
	PSPH	ENST00000395471.7	TSL:1	c.275+1delG		splice_donor intron	N/A	ENSP00000378854.3
	PSPH	ENST00000421626.5	TSL:4	c.275+1delG		splice_donor intron	N/A	ENSP00000398653.1

Frequencies

GnomAD3 genomes AF: 0.242 AC: 31704 AN: 131022 Hom.: 0 Cov.: 0

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: 9 AN: 239758 AF XY: 0.0000386

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.: 0 Cov.: 30 AF XY: 0.0296 AC XY: 17130 AN XY: 579328

⚠️ 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), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ 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: 32 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), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.151 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	1	-	Neurometabolic disorder due to serine deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=16/84	disease causing

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

Other links and lift over

dbSNP: rs139106189; hg19: chr7-56087291; COSMIC: COSV51910657; COSMIC: COSV51910657;