rs73343752

Variant names:

• chr7-56011790-A-G
• rs73343752
• NM_004577.4:c.650T>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V217V) has been classified as Likely benign.

• 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
• Publications: 3 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• neurometabolic disorder due to serine deficiency

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 391900.
• 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

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.650T>C	p.Val217Ala	missense	Exon 8 of 8	NP_004568.2
	PSPH	NM_001370503.1		c.650T>C	p.Val217Ala	missense	Exon 8 of 8	NP_001357432.1
	PSPH	NM_001370504.1		c.650T>C	p.Val217Ala	missense	Exon 8 of 8	NP_001357433.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSPH	ENST00000275605.8	TSL:1 MANE Select	c.650T>C	p.Val217Ala	missense	Exon 8 of 8	ENSP00000275605.3
	PSPH	ENST00000395471.7	TSL:1	c.650T>C	p.Val217Ala	missense	Exon 8 of 8	ENSP00000378854.3
	PSPH	ENST00000891724.1		c.650T>C	p.Val217Ala	missense	Exon 8 of 8	ENSP00000561783.1

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

GnomAD2 exomes AF: 0.00188 AC: 472 AN: 251138 AF XY: 0.00136

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 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

African (AFR) AF: 0.0231 AC: 773 AN: 33436

American (AMR) AF: 0.00161 AC: 72 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5756

European-Non Finnish (NFE) AF: 0.0000549 AC: 61 AN: 1111320

Other (OTH) AF: 0.00169 AC: 102 AN: 60364

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

African (AFR) AF: 0.0246 AC: 1021 AN: 41574

American (AMR) AF: 0.00360 AC: 55 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.00291 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

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Deficiency of phosphoserine phosphatase (3)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.90	N
PhyloP100		1.3
PrimateAI	Benign	0.36	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.12
Sift	Benign	0.67	T
Sift4G	Benign	0.81	T
Polyphen		0.0	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
Mutation Taster		=91/9	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: rs73343752; hg19: chr7-56079483;