Genetic Variant PSAP:p.Gln430Lys (chr10-71819527-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002778.4(PSAP):c.1288C>A(p.Gln430Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PSAP
NM_002778.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.168

Variant links:

Genes affected

PSAP (HGNC:9498): (prosaposin) This gene encodes a highly conserved preproprotein that is proteolytically processed to generate four main cleavage products including saposins A, B, C, and D. Each domain of the precursor protein is approximately 80 amino acid residues long with nearly identical placement of cysteine residues and glycosylation sites. Saposins A-D localize primarily to the lysosomal compartment where they facilitate the catabolism of glycosphingolipids with short oligosaccharide groups. The precursor protein exists both as a secretory protein and as an integral membrane protein and has neurotrophic activities. Mutations in this gene have been associated with Gaucher disease and metachromatic leukodystrophy. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

PSAP links:

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ACMG classification

Classification made for transcript

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=0.07735944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSAP	NM_002778.4 link	c.1288C>A	p.Gln430Lys	missense_variant	Exon 11 of 14	ENST00000394936.8	NP_002769.1	P07602-1A0A024QZQ2
PSAP	NM_001042465.3 link	c.1297C>A	p.Gln433Lys	missense_variant	Exon 12 of 15		NP_001035930.1	P07602-3
PSAP	NM_001042466.3 link	c.1294C>A	p.Gln432Lys	missense_variant	Exon 12 of 15		NP_001035931.1	P07602-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSAP	ENST00000394936.8 link	c.1288C>A	p.Gln430Lys	missense_variant	Exon 11 of 14	1	NM_002778.4	ENSP00000378394.3		P07602-1
PSAP	ENST00000493143.1 link	n.*224C>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.38

T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.81

T;D;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.077

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.82

L;.;.

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.82

N;.;.

REVEL

Benign

0.25

Sift

Benign

0.48

T;.;.

Sift4G

Benign

0.88

T;T;T

Polyphen

0.015

B;.;.

Vest4

0.20

MutPred

0.48

Gain of ubiquitination at Q430 (P = 0.0192);.;.;

MVP

0.44

MPC

0.051

ClinPred

0.036

GERP RS

-4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over