Genetic Variant SKA1:p.Leu52Phe (chr18-50380191-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_145060.4(SKA1):c.154C>T(p.Leu52Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,402,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SKA1
NM_145060.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.92

Variant links:

Genes affected

SKA1 (HGNC:28109): (spindle and kinetochore associated complex subunit 1) Enables microtubule binding activity. Involved in several processes, including chromosome segregation; mitotic cell cycle; and regulation of microtubule polymerization or depolymerization. Located in spindle microtubule. Part of outer kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

SKA1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SKA1	NM_145060.4 link	c.154C>T	p.Leu52Phe	missense_variant	Exon 3 of 7	ENST00000285116.8	NP_659497.1	Q96BD8-1A0A024R294
SKA1	NM_001039535.3 link	c.154C>T	p.Leu52Phe	missense_variant	Exon 3 of 7		NP_001034624.1	Q96BD8-1A0A024R294

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SKA1	ENST00000285116.8 link	c.154C>T	p.Leu52Phe	missense_variant	Exon 3 of 7	5	NM_145060.4	ENSP00000285116.3		Q96BD8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000101

AC:

AN:

197102

Hom.:

AF XY:

0.00

AC XY:

AN XY:

108170

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000990

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1402148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697048

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000670

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:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.154C>T (p.L52F) alteration is located in exon 3 (coding exon 2) of the SKA1 gene. This alteration results from a C to T substitution at nucleotide position 154, causing the leucine (L) at amino acid position 52 to be replaced by a phenylalanine (F). 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

0.14

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.060

T;T;.

Eigen

Benign

-0.051

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.68

.;T;T

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.6

M;M;M

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.094

Sift

Benign

0.050

D;D;D

Sift4G

Benign

0.065

T;T;T

Polyphen

0.041

B;B;B

Vest4

0.34

MutPred

0.85

Loss of catalytic residue at L52 (P = 0.0564);Loss of catalytic residue at L52 (P = 0.0564);Loss of catalytic residue at L52 (P = 0.0564);

MVP

0.66

MPC

0.48

ClinPred

0.76

GERP RS

4.2

Varity_R

0.23

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

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