Genetic Variant SKA3:p.Glu71Gln (chr13-21172459-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_145061.6(SKA3):c.211G>C(p.Glu71Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,437,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 35)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

SKA3
NM_145061.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

Variant links:

Genes affected

SKA3 (HGNC:20262): (spindle and kinetochore associated complex subunit 3) This gene encodes a component of the spindle and kinetochore-associated protein complex that regulates microtubule attachment to the kinetochores during mitosis. The encoded protein localizes to the outer kinetechore and may be required for normal chromosome segregation and cell division. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

SKA3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25881258).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKA3	NM_145061.6 link	c.211G>C	p.Glu71Gln	missense_variant	Exon 3 of 9	ENST00000314759.6	NP_659498.4	Q8IX90-1
SKA3	NM_001166017.2 link	c.211G>C	p.Glu71Gln	missense_variant	Exon 3 of 8		NP_001159489.1	Q8IX90-3
SKA3	XM_011534994.3 link	c.91G>C	p.Glu31Gln	missense_variant	Exon 3 of 9		XP_011533296.1
SKA3	XM_005266288.5 link	c.-36G>C		5_prime_UTR_variant	Exon 2 of 8		XP_005266345.1	Q8IX90

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKA3	ENST00000314759.6 link	c.211G>C	p.Glu71Gln	missense_variant	Exon 3 of 9	1	NM_145061.6	ENSP00000319417.5		Q8IX90-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000443

AC:

AN:

225612

Hom.:

AF XY:

0.00000816

AC XY:

AN XY:

122582

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000589

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000348

AC:

AN:

1437544

Hom.:

Cov.:

AF XY:

0.00000559

AC XY:

AN XY:

715168

show subpopulations

Gnomad4 AFR exome

AF:

0.0000628

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:

0.00

Gnomad4 OTH exome

AF:

0.0000505

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 05, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.211G>C (p.E71Q) alteration is located in exon 3 (coding exon 3) of the SKA3 gene. This alteration results from a G to C substitution at nucleotide position 211, causing the glutamic acid (E) at amino acid position 71 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

Benign

0.13

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

.;T

Eigen

Benign

0.17

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.5

M;M

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.9

N;N

REVEL

Benign

0.12

Sift

Benign

0.031

D;D

Sift4G

Benign

0.11

T;T

Polyphen

0.98

D;D

Vest4

0.39

MutPred

0.38

Gain of catalytic residue at I73 (P = 0.0455);Gain of catalytic residue at I73 (P = 0.0455);

MVP

0.48

MPC

0.48

ClinPred

0.95

GERP RS

4.7

Varity_R

0.27

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over