7-56011767-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004577.4(PSPH):c.673G>A(p.Glu225Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,609,488 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E225Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: PSPH NM_004577.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.029164135).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PSPH	NM_004577.4	c.673G>A	p.Glu225Lys	missense_variant	8/8	ENST00000275605.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PSPH	ENST00000275605.8	c.673G>A	p.Glu225Lys	missense_variant	8/8	1	NM_004577.4	P1
PSPH	ENST00000395471.7	c.673G>A	p.Glu225Lys	missense_variant	8/8	1		P1
PSPH	ENST00000459834.5	n.463G>A		non_coding_transcript_exon_variant	3/3	3
PSPH	ENST00000437355.6	c.673G>A	p.Glu225Lys	missense_variant, NMD_transcript_variant	6/7	5

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152072 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251140 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000117 AC: 170 AN: 1457298 Hom.: 0 Cov.: 30 AF XY: 0.000116 AC XY: 84 AN XY: 725290

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000136

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152190 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74414

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of phosphoserine phosphatase Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 225 of the PSPH protein (p.Glu225Lys). This variant is present in population databases (rs536712417, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PSPH-related conditions. ClinVar contains an entry for this variant (Variation ID: 1357241). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The lysine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2021

The c.673G>A (p.E225K) alteration is located in exon 8 (coding exon 5) of the PSPH gene. This alteration results from a G to A substitution at nucleotide position 673, causing the glutamic acid (E) at amino acid position 225 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	15
Dann	Benign	0.94
DEOGEN2	Benign	0.0029	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.029	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	-1.6	N;N
MutationTaster	Benign	0.62	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.24
Sift	Benign	0.45	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.0	B;B
Vest4		0.19
MutPred		0.37		Gain of ubiquitination at E225 (P = 0.0177);Gain of ubiquitination at E225 (P = 0.0177);
MVP		0.13
MPC		0.24
ClinPred		0.045	T
GERP RS		3.8
Varity_R		0.20
gMVP		0.76

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;