7-56011767-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSPH	NM_004577.4	c.673G>C	p.Glu225Gln	missense_variant	Exon 8 of 8	ENST00000275605.8	NP_004568.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSPH	ENST00000275605.8	c.673G>C	p.Glu225Gln	missense_variant	Exon 8 of 8	1	NM_004577.4	ENSP00000275605.3
PSPH	ENST00000395471.7	c.673G>C	p.Glu225Gln	missense_variant	Exon 8 of 8	1		ENSP00000378854.3
PSPH	ENST00000437355.6	n.673G>C		non_coding_transcript_exon_variant	Exon 6 of 7	5		ENSP00000401639.2
PSPH	ENST00000459834.5	n.463G>C		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of phosphoserine phosphatase Uncertain:1

Nov 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 999748). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PSPH-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 225 of the PSPH protein (p.Glu225Gln). This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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;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;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.21	N;N
REVEL	Benign	0.21
Sift	Benign	0.16	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0020	B;B
Vest4		0.18
MutPred		0.37		Loss of disorder (P = 0.1677);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs536712417; hg19: chr7-56079460;