NM_004577.4:c.267dupC

Variant names:

• chr7-56019607-C-CG
• rs587777773
• NM_004577.4:c.267dupC

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_004577.4(PSPH):​c.267dupC​(p.Gly90ArgfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,666 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 36)
• Consequence: PSPH NM_004577.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• neurometabolic disorder due to serine deficiency

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004577.4. 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
	PSPH	NM_004577.4	MANE Select	c.267dupC	p.Gly90ArgfsTer24	frameshift	Exon 5 of 8	NP_004568.2
	PSPH	NM_001370503.1		c.267dupC	p.Gly90ArgfsTer24	frameshift	Exon 5 of 8	NP_001357432.1	P78330
	PSPH	NM_001370504.1		c.267dupC	p.Gly90ArgfsTer24	frameshift	Exon 5 of 8	NP_001357433.1	P78330

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSPH	ENST00000275605.8	TSL:1 MANE Select	c.267dupC	p.Gly90ArgfsTer24	frameshift	Exon 5 of 8	ENSP00000275605.3	P78330
	PSPH	ENST00000395471.7	TSL:1	c.267dupC	p.Gly90ArgfsTer24	frameshift	Exon 5 of 8	ENSP00000378854.3	P78330
	PSPH	ENST00000891724.1		c.267dupC	p.Gly90ArgfsTer24	frameshift	Exon 5 of 8	ENSP00000561783.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151666 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151666 Hom.: 0 Cov.: 36 AF XY: 0.0000135 AC XY: 1 AN XY: 74024

African (AFR) AF: 0.0000242 AC: 1 AN: 41338

American (AMR) AF: 0.00 AC: 0 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67884

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
Mutation Taster		=11/189	disease causing (fs/PTC)

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: rs587777773; hg19: chr7-56087300;