13-21158125-C-A

Variant names:

• chr13-21158125-C-A
• rs764380078
• NM_145061.6:c.916G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145061.6(SKA3):​c.916G>T​(p.Val306Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,401,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V306I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SKA3 NM_145061.6 missense, splice_region
• Scores: Splicing: ADA: 0.8780
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.170
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015375167).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145061.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKA3	NM_145061.6	MANE Select	c.916G>T	p.Val306Leu	missense splice_region	Exon 7 of 9	NP_659498.4
	SKA3	NM_001166017.2		c.916G>T	p.Val306Leu	missense splice_region	Exon 7 of 8	NP_001159489.1	Q8IX90-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SKA3	ENST00000314759.6	TSL:1 MANE Select	c.916G>T	p.Val306Leu	missense splice_region	Exon 7 of 9	ENSP00000319417.5	Q8IX90-1
	SKA3	ENST00000921404.1		c.916G>T	p.Val306Leu	missense splice_region	Exon 7 of 9	ENSP00000591463.1
	SKA3	ENST00000921408.1		c.859G>T	p.Val287Leu	missense splice_region	Exon 7 of 9	ENSP00000591467.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245618 AF XY: 0.00000752

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 FIN exome AF: 0.0000954

Gnomad NFE exome AF: 0.00000901

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1401062 Hom.: 0 Cov.: 28 AF XY: 0.00000286 AC XY: 2 AN XY: 700442

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32172

American (AMR) AF: 0.00 AC: 0 AN: 44404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25682

East Asian (EAS) AF: 0.00 AC: 0 AN: 39314

South Asian (SAS) AF: 0.00 AC: 0 AN: 84752

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5412

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057864

Other (OTH) AF: 0.0000171 AC: 1 AN: 58366

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ExAC AF: 0.000173 AC: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.83
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.17
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.023
Sift	Benign	0.69	T
Sift4G	Benign	0.69	T
Polyphen		0.10	B
Vest4		0.027
MutPred		0.26		Gain of catalytic residue at L305 (P = 5e-04)
MVP		0.14
MPC		0.12
ClinPred		0.037	T
GERP RS		1.7
Varity_R		0.055
gMVP		0.14
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.52
SpliceAI score (max)		0.18		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs764380078; hg19: chr13-21732264;