17-3610588-C-A

Variant names:

• chr17-3610588-C-A
• rs1020355454
• NM_013276.4:c.1409G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013276.4(SHPK):​c.1409G>T​(p.Arg470Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R470W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SHPK NM_013276.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.109
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• isolated sedoheptulokinase deficiency

  Inheritance: AR, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ENSG00000262304 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07891071).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013276.4. 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
	SHPK	NM_013276.4	MANE Select	c.1409G>T	p.Arg470Leu	missense	Exon 7 of 7	NP_037408.2	Q9UHJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHPK	ENST00000225519.5	TSL:1 MANE Select	c.1409G>T	p.Arg470Leu	missense	Exon 7 of 7	ENSP00000225519.3	Q9UHJ6
	ENSG00000262304	ENST00000572919.1	TSL:5	n.1409G>T		non_coding_transcript_exon	Exon 7 of 14	ENSP00000461416.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456034 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723104

African (AFR) AF: 0.00 AC: 0 AN: 33380

American (AMR) AF: 0.00 AC: 0 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26030

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107424

Other (OTH) AF: 0.00 AC: 0 AN: 60184

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.6
DANN	Benign	0.96
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.48	N
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.99	T
PhyloP100		-0.11
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.15
Sift	Benign	0.33	T
Sift4G	Benign	0.095	T
Vest4		0.13
MutPred		0.49		Loss of MoRF binding (P = 0.006)
MVP		0.13
MPC		0.36
ClinPred		0.11	T
GERP RS		-6.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.25

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

Other links and lift over

dbSNP: rs1020355454; hg19: chr17-3513882;