chr1-45345169-A-T

Variant names:

• chr1-45345169-A-T
• NM_007170.3:c.1387T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007170.3(TESK2):​c.1387T>A​(p.Phe463Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TESK2 NM_007170.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88
• Publications: 0 publications found

Genes affected

TESK2 (HGNC:11732): (testis associated actin remodelling kinase 2) This gene product is a serine/threonine protein kinase that contains an N-terminal protein kinase domain that is structurally similar to the kinase domains of testis-specific protein kinase-1 and the LIM motif-containing protein kinases (LIMKs). Its overall structure is most related to the former, indicating that it belongs to the TESK subgroup of the LIMK/TESK family of protein kinases. This gene is predominantly expressed in testis and prostate. The developmental expression pattern of the rat gene in testis suggests an important role for this gene in meitoic stages and/or early stages of spermiogenesis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ENSG00000288208 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15100315).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TESK2	NM_007170.3	c.1387T>A	p.Phe463Ile	missense_variant	Exon 11 of 11	ENST00000372086.4	NP_009101.2
TESK2	NM_001320800.2	c.1138T>A	p.Phe380Ile	missense_variant	Exon 10 of 10		NP_001307729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TESK2	ENST00000372086.4	c.1387T>A	p.Phe463Ile	missense_variant	Exon 11 of 11	1	NM_007170.3	ENSP00000361158.3
TESK2	ENST00000372084.5	c.1300T>A	p.Phe434Ile	missense_variant	Exon 9 of 9	1		ENSP00000361156.1
ENSG00000288208	ENST00000671898.1	n.540+10134T>A		intron_variant	Intron 5 of 20			ENSP00000499896.1
TESK2	ENST00000486676.5	n.1734T>A		non_coding_transcript_exon_variant	Exon 10 of 10	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1387T>A (p.F463I) alteration is located in exon 11 (coding exon 10) of the TESK2 gene. This alteration results from a T to A substitution at nucleotide position 1387, causing the phenylalanine (F) at amino acid position 463 to be replaced by an isoleucine (I). 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	0.086
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.014	.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.016
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.8	.;L
PhyloP100		2.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.22
Sift	Uncertain	0.017	D;D
Sift4G	Benign	0.094	T;T
Polyphen		0.20	B;B
Vest4		0.19
MutPred		0.066		.;Loss of catalytic residue at P461 (P = 0.1992);
MVP		0.81
MPC		0.28
ClinPred		0.51	D
GERP RS		5.9
Varity_R		0.10
gMVP		0.10
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

hg19: chr1-45810841;