5-134161060-C-T

Position:

• chr5-134161060-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_170679.3(SKP1):​c.242G>A​(p.Arg81Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: SKP1 NM_170679.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.35349378).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SKP1	NM_170679.3	c.242G>A	p.Arg81Gln	missense_variant	4/6	ENST00000353411.11	NP_733779.1
SKP1	NM_006930.4	c.242G>A	p.Arg81Gln	missense_variant	4/5		NP_008861.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SKP1	ENST00000353411.11	c.242G>A	p.Arg81Gln	missense_variant	4/6	1	NM_170679.3	ENSP00000231487.9
ENSG00000272772	ENST00000519718.2	c.344G>A	p.Arg115Gln	missense_variant	4/6	5		ENSP00000430774.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251356 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135870

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460668 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726704

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: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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

Aug 13, 2021

The c.242G>A (p.R81Q) alteration is located in exon 4 (coding exon 3) of the SKP1 gene. This alteration results from a G to A substitution at nucleotide position 242, causing the arginine (R) at amino acid position 81 to be replaced by a glutamine (Q). 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	0.89
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T;.;T;T;T;T;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D;.;D;D;D;D
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.2	M;M;.;M;M;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D
REVEL	Benign	0.20
Sift	Benign	0.10	T;T;T;T;T;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T;.;.;T
Polyphen		0.0010	B;B;B;B;B;.;.;.
Vest4		0.56
MutPred		0.32		Loss of methylation at K80 (P = 0.0906);Loss of methylation at K80 (P = 0.0906);Loss of methylation at K80 (P = 0.0906);Loss of methylation at K80 (P = 0.0906);Loss of methylation at K80 (P = 0.0906);Loss of methylation at K80 (P = 0.0906);Loss of methylation at K80 (P = 0.0906);Loss of methylation at K80 (P = 0.0906);
MVP		0.56
MPC		1.8
ClinPred		0.89	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.89

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: rs1176681263; hg19: chr5-133496751;