rs144071313

Positions:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_013276.4(SHPK):c.355C>T(p.Arg119Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000743 in 1,614,038 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 2 hom. )

Consequence

SHPK
NM_013276.4 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1O:1

Conservation

PhyloP100: -0.272

Variant links:

Genes affected

SHPK (HGNC:1492): (sedoheptulokinase) The protein encoded by this gene has weak homology to several carbohydrate kinases, a class of proteins involved in the phosphorylation of sugars as they enter a cell, inhibiting return across the cell membrane. Sequence variation between this novel gene and known carbohydrate kinases suggests the possibility of a different substrate, cofactor or changes in kinetic properties distinguishing it from other carbohydrate kinases. The gene resides in a region commonly deleted in cystinosis patients, suggesting a role as a modifier for the cystinosis phenotype. The genomic region is also rich in Alu repetitive sequences, frequently involved in chromosomal rearrangements. [provided by RefSeq, Jul 2008]

SHPK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHPK	NM_013276.4 linkuse as main transcript	c.355C>T	p.Arg119Ter	stop_gained	3/7	ENST00000225519.5	NP_037408.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHPK	ENST00000225519.5 linkuse as main transcript	c.355C>T	p.Arg119Ter	stop_gained	3/7	1	NM_013276.4	ENSP00000225519	P1

Frequencies

GnomAD3 genomes

AF:

0.000572

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000545

AC:

137

AN:

251228

Hom.:

AF XY:

0.000545

AC XY:

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000666

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000933

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000761

AC:

1112

AN:

1461738

Hom.:

Cov.:

AF XY:

0.000714

AC XY:

519

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000934

Gnomad4 OTH exome

AF:

0.000646

GnomAD4 genome

AF:

0.000571

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000591

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.000764

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000901

Hom.:

Bravo

AF:

0.000695

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000502

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.000948

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

This sequence change creates a premature translational stop signal (p.Arg119*) in the SHPK gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SHPK cause disease. This variant is present in population databases (rs144071313, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with sedoheptulokinase deficiency (PMID: 25647543). ClinVar contains an entry for this variant (Variation ID: 372202). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects SHPK function (PMID: 25647543). 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. -

Isolated sedoheptulokinase deficiency

Other:1

Affects, no assertion criteria provided

literature only

OMIM

Nov 22, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Benign

0.95

Eigen

Benign

-0.72

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.083

MutationTaster

Benign

1.0

Vest4

0.17

GERP RS

-5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over