NM_004577.4:c.673G>C

Variant names:

• chr7-56011767-C-G
• rs536712417
• NM_004577.4:c.673G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004577.4(PSPH):​c.673G>C​(p.Glu225Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E225K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PSPH NM_004577.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.20
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0787234).

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.673G>C	p.Glu225Gln	missense	Exon 8 of 8	NP_004568.2
	PSPH	NM_001370503.1		c.673G>C	p.Glu225Gln	missense	Exon 8 of 8	NP_001357432.1	P78330
	PSPH	NM_001370504.1		c.673G>C	p.Glu225Gln	missense	Exon 8 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.673G>C	p.Glu225Gln	missense	Exon 8 of 8	ENSP00000275605.3	P78330
	PSPH	ENST00000395471.7	TSL:1	c.673G>C	p.Glu225Gln	missense	Exon 8 of 8	ENSP00000378854.3	P78330
	PSPH	ENST00000891724.1		c.673G>C	p.Glu225Gln	missense	Exon 8 of 8	ENSP00000561783.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Deficiency of phosphoserine phosphatase (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.072	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.0030	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.21
Sift	Benign	0.16	T
Sift4G	Benign	0.18	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.37		Loss of disorder (P = 0.1677)
MVP		0.33
MPC		0.21
ClinPred		0.23	T
GERP RS		3.8
Varity_R		0.31
gMVP		0.70
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs536712417; hg19: chr7-56079460;