17-3610760-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_013276.4(SHPK):c.1237A>G(p.Met413Val) variant causes a missense change. The variant allele was found at a frequency of 0.00543 in 1,614,056 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0055 (33 hom.)
• Consequence: SHPK NM_013276.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.00

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010470659).
• BP6: Variant 17-3610760-T-C is Benign according to our data. Variant chr17-3610760-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 786430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHPK	NM_013276.4	c.1237A>G	p.Met413Val	missense_variant	7/7	ENST00000225519.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHPK	ENST00000225519.5	c.1237A>G	p.Met413Val	missense_variant	7/7	1	NM_013276.4	P1

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 756 AN: 152124 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00822

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00427 AC: 1074 AN: 251282 Hom.: 3 AF XY: 0.00417 AC XY: 566 AN XY: 135806

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00824

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00264

Gnomad NFE exome AF: 0.00730

Gnomad OTH exome AF: 0.00490

GnomAD4 exome AF: 0.00548 AC: 8004 AN: 1461814 Hom.: 33 Cov.: 32 AF XY: 0.00530 AC XY: 3853 AN XY: 727204

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00750

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00320

Gnomad4 NFE exome AF: 0.00647

Gnomad4 OTH exome AF: 0.00480

GnomAD4 genome AF: 0.00496 AC: 755 AN: 152242 Hom.: 7 Cov.: 33 AF XY: 0.00466 AC XY: 347 AN XY: 74438

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00349

Gnomad4 NFE AF: 0.00822

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00614 Hom.: 4

Bravo AF: 0.00468

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00872 AC: 75

ExAC AF: 0.00442 AC: 537

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00774

EpiControl AF: 0.00711

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	SHPK: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	22
Dann	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0090	D
Vest4		0.74
MVP		0.23
MPC		0.85
ClinPred		0.019	T
GERP RS		4.9
gMVP		0.74

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: rs35091524; hg19: chr17-3514054; COSMIC: COSV99843605; COSMIC: COSV99843605;