5-134161048-A-G

Position:

• chr5-134161048-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_170679.3(SKP1):​c.254T>C​(p.Ile85Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,492 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SKP1 NM_170679.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.68

Genes affected

SKP1 (HGNC:10899): (S-phase kinase associated protein 1) This gene encodes a component of SCF complexes, which are composed of this protein, cullin 1, a ring-box protein, and one member of the F-box family of proteins. This protein binds directly to the F-box motif found in F-box proteins. SCF complexes are involved in the regulated ubiquitination of specific protein substrates, which targets them for degradation by the proteosome. Specific F-box proteins recognize different target protein(s), and many specific SCF substrates have been identified including regulators of cell cycle progression and development. Studies have also characterized the protein as an RNA polymerase II elongation factor. Alternative splicing of this gene results in two transcript variants. A related pseudogene has been identified on chromosome 7. [provided by RefSeq, Jul 2008]

ENSG00000272772 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKP1	NM_170679.3	c.254T>C	p.Ile85Thr	missense_variant	4/6	ENST00000353411.11	NP_733779.1
SKP1	NM_006930.4	c.254T>C	p.Ile85Thr	missense_variant	4/5		NP_008861.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKP1	ENST00000353411.11	c.254T>C	p.Ile85Thr	missense_variant	4/6	1	NM_170679.3	ENSP00000231487.9
ENSG00000272772	ENST00000519718.2	c.356T>C	p.Ile119Thr	missense_variant	4/6	5		ENSP00000430774.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460492 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726612

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2024

The c.254T>C (p.I85T) alteration is located in exon 4 (coding exon 3) of the SKP1 gene. This alteration results from a T to C substitution at nucleotide position 254, causing the isoleucine (I) at amino acid position 85 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T;T;T;T;.;T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;.;D;D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.076	T
MutationAssessor	Pathogenic	3.5	M;M;.;M;M;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.8	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;.;.;D
Polyphen		0.14	B;D;D;B;B;.;.;.
Vest4		0.81
MutPred		0.68		Gain of disorder (P = 0.0126);Gain of disorder (P = 0.0126);Gain of disorder (P = 0.0126);Gain of disorder (P = 0.0126);Gain of disorder (P = 0.0126);Gain of disorder (P = 0.0126);Gain of disorder (P = 0.0126);Gain of disorder (P = 0.0126);
MVP		0.81
MPC		2.9
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.96

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.

Other links and lift over

hg19: chr5-133496739;