chr19-49739831-C-T

Variant names:

• chr19-49739831-C-T
• rs1568558922
• NM_021733.2:c.1724G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021733.2(TSKS):​c.1724G>A​(p.Gly575Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,872 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: 6.9e-7 (0 hom.)
• Consequence: TSKS NM_021733.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00

Genes affected

TSKS (HGNC:30719): (testis specific serine kinase substrate) This gene may play a role in testicular physiology, spermatogenesis or spermiogenesis. Expression of the encoded protein is highest in the testis and down-regulated in testicular cancer. The gene is localized to the region 19q13.3 among the related RAS viral oncogene homolog (RRAS) and interferon regulatory factor 3 (IRF3) genes, which are both involved in tumorigenesis pathways and progression. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41718143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSKS	NM_021733.2	c.1724G>A	p.Gly575Glu	missense_variant	Exon 11 of 11	ENST00000246801.8	NP_068379.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSKS	ENST00000246801.8	c.1724G>A	p.Gly575Glu	missense_variant	Exon 11 of 11	1	NM_021733.2	ENSP00000246801.2
TSKS	ENST00000358830.3	c.1124G>A	p.Gly375Glu	missense_variant	Exon 7 of 7	1		ENSP00000351691.2
TSKS	ENST00000599325.1	n.501G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458872 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725938

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1724G>A (p.G575E) alteration is located in exon 11 (coding exon 11) of the TSKS gene. This alteration results from a G to A substitution at nucleotide position 1724, causing the glycine (G) at amino acid position 575 to be replaced by a glutamic acid (E). 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	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.091	T;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.42	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.1	L;.
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.27
Sift	Benign	0.10	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.59
MutPred		0.12		Gain of solvent accessibility (P = 0.0456);.;
MVP		0.40
MPC		0.91
ClinPred		0.92	D
GERP RS		4.9
Varity_R		0.26
gMVP		0.060

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: rs1568558922; hg19: chr19-50243088; COSMIC: COSV55879896;