rs73343752

Positions:

• chr7-56011790-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_004577.4(PSPH):​c.650T>C​(p.Val217Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,360 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0072 (11 hom., cov: 31)
  • Exomes 𝑓: 0.00070 (9 hom.)
• Consequence: PSPH NM_004577.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.26

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036592782).
• BP6: Variant 7-56011790-A-G is Benign according to our data. Variant chr7-56011790-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 391900.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}. Variant chr7-56011790-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00721 (1098/152316) while in subpopulation AFR AF= 0.0246 (1021/41574). AF 95% confidence interval is 0.0233. There are 11 homozygotes in gnomad4. There are 523 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSPH	NM_004577.4	c.650T>C	p.Val217Ala	missense_variant	8/8	ENST00000275605.8	NP_004568.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSPH	ENST00000275605.8	c.650T>C	p.Val217Ala	missense_variant	8/8	1	NM_004577.4	ENSP00000275605.3
PSPH	ENST00000395471.7	c.650T>C	p.Val217Ala	missense_variant	8/8	1		ENSP00000378854.3
PSPH	ENST00000437355.6	n.650T>C		non_coding_transcript_exon_variant	6/7	5		ENSP00000401639.2
PSPH	ENST00000459834.5	n.440T>C		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.00722 AC: 1099 AN: 152198 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

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: 0.0000588

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00188 AC: 472 AN: 251138 Hom.: 3 AF XY: 0.00136 AC XY: 185 AN XY: 135740

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000701 AC: 1024 AN: 1461044 Hom.: 9 Cov.: 30 AF XY: 0.000592 AC XY: 430 AN XY: 726866

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000549

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00721 AC: 1098 AN: 152316 Hom.: 11 Cov.: 31 AF XY: 0.00702 AC XY: 523 AN XY: 74488

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.000988 Hom.: 1

Bravo AF: 0.00833

ESP6500AA AF: 0.0256 AC: 113

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00236 AC: 286

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of phosphoserine phosphatase Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2017

The V217A variant in the PSPH gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports V217A was observed in 113/4,406 alleles (2.6%) from individuals of African American background. The V217A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret V217A as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.7
DANN	Benign	0.37
DEOGEN2	Benign	0.0042	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.63	.;T
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.90	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.0	N;N
REVEL	Benign	0.12
Sift	Benign	0.67	T;T
Sift4G	Benign	0.81	T;T
Polyphen		0.0	B;B
Vest4		0.063
MVP		0.14
MPC		0.26
ClinPred		0.0013	T
GERP RS		0.80
Varity_R		0.075
gMVP		0.35

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: rs73343752; hg19: chr7-56079483;