17-3623343-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_013276.4(SHPK):c.643G>A(p.Glu215Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,613,856 control chromosomes in the GnomAD database, including 19,206 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (4854 hom., cov: 33)
  • Exomes 𝑓: 0.12 (14352 hom.)
• Consequence: SHPK NM_013276.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.47

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061131716).
• BP6: Variant 17-3623343-C-T is Benign according to our data. Variant chr17-3623343-C-T is described in ClinVar as [Benign]. Clinvar id is 1166170.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHPK	NM_013276.4	c.643G>A	p.Glu215Lys	missense_variant	4/7	ENST00000225519.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHPK	ENST00000225519.5	c.643G>A	p.Glu215Lys	missense_variant	4/7	1	NM_013276.4	P1

Frequencies

GnomAD3 genomes AF: 0.204 AC: 31085 AN: 152032 Hom.: 4835 Cov.: 33

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.0810

Gnomad EAS AF: 0.219

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.0756

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.171

GnomAD3 exomes AF: 0.151 AC: 37890 AN: 251358 Hom.: 4050 AF XY: 0.147 AC XY: 19980 AN XY: 135864

Gnomad AFR exome AF: 0.446

Gnomad AMR exome AF: 0.143

Gnomad ASJ exome AF: 0.0807

Gnomad EAS exome AF: 0.227

Gnomad SAS exome AF: 0.223

Gnomad FIN exome AF: 0.0804

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.122 AC: 178037 AN: 1461708 Hom.: 14352 Cov.: 33 AF XY: 0.123 AC XY: 89142 AN XY: 727172

Gnomad4 AFR exome AF: 0.460

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.0826

Gnomad4 EAS exome AF: 0.218

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.0820

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.140

GnomAD4 genome AF: 0.205 AC: 31157 AN: 152148 Hom.: 4854 Cov.: 33 AF XY: 0.203 AC XY: 15113 AN XY: 74396

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.155

Gnomad4 ASJ AF: 0.0810

Gnomad4 EAS AF: 0.220

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.0756

Gnomad4 NFE AF: 0.101

Gnomad4 OTH AF: 0.179

Alfa AF: 0.118 Hom.: 3771

Bravo AF: 0.222

TwinsUK AF: 0.100 AC: 371

ALSPAC AF: 0.106 AC: 409

ESP6500AA AF: 0.434 AC: 1912

ESP6500EA AF: 0.0967 AC: 832

ExAC AF: 0.158 AC: 19164

Asia WGS AF: 0.312 AC: 1088 AN: 3478

EpiCase AF: 0.0920

EpiControl AF: 0.0933

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	-0.065
Eigen_PC	Benign	-0.035
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	0.80	P
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.077
Sift	Benign	0.030	D
Sift4G	Benign	0.089	T
Vest4		0.13
MPC		0.45
ClinPred		0.021	T
GERP RS		4.1
gMVP		0.54

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

LitVar

Other links and lift over

dbSNP: rs150857; hg19: chr17-3526637; COSMIC: COSV56649135; COSMIC: COSV56649135;