chr2-171007045-G-C

Position:

• chr2-171007045-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_012290.5(TLK1):​c.1435C>G​(p.Gln479Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLK1 NM_012290.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 10.0

Genes affected

TLK1 (HGNC:11841): (tousled like kinase 1) The protein encoded by this gene is a serine/threonine kinase that may be involved in the regulation of chromatin assembly. The encoded protein is only active when it is phosphorylated, and this phosphorylation is cell cycle-dependent, with the maximal activity of this protein coming during S phase. The catalytic activity of this protein is diminished by DNA damage and by blockage of DNA replication. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TLK1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLK1	NM_012290.5	c.1435C>G	p.Gln479Glu	missense_variant	15/21	ENST00000431350.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLK1	ENST00000431350.7	c.1435C>G	p.Gln479Glu	missense_variant	15/21	1	NM_012290.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 12, 2023

The p.Gln479Glu variant in TLK1 has been reported de novo by whole genome sequencing in a male child with white matter disease, global developmental delay, intellectual disability, hypothyroidism, and primary immunodeficiency (Villamor-Payà 2023 DOI: 10.1101/2023.08.22.23294267; Broad Institute Rare Genomes Project). It was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In vitro functional studies provide some evidence that this variant impacts protein function (Villamor-Payà 2023 DOI: 10.1101/2023.08.22.23294267); however, these types of assays may not accurately represent biological function. Furthermore, although this gene has been reported in association with a neurodevelopmental disorder, it currently has limited evidence for this association. In summary, the clinical significance of this variant is uncertain. -

Neurodevelopmental disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Aug 30, 2023

The heterozygous p.Gln479Glu variant in TLK1 was identified in one individual with microcephaly, intellectual disability, seizures, global developmental delay, cerebral calcifications, feeding difficulties, growth hormone deficiency, hypothyroidism, urticaria, mild retinal dystrophy, and primary immunodeficiency (DOI: 10.1101/2023.08.22.23294267). Trio genome analysis through the Rare Genomes Project showed this variant to be de novo. The variant was absent from large population studies. In vitro functional studies provide some evidence that the p.Gln479Glu variant may impact protein function (DOI: 10.1101/2023.08.22.23294267). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. Furthermore, although this gene has been reported in association with neurodevelopmental disorders, it currently has limited evidence for these associations. In summary, the clinical significance of the p.Gln479Glu variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.088	T;.;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.53	N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.024	D;D;D;D
Sift4G	Benign	0.099	T;T;T;T
Polyphen		0.34	B;B;.;.
Vest4		0.72
MutPred		0.52		Loss of MoRF binding (P = 0.0568);.;.;.;
MVP		0.75
MPC		1.6
ClinPred		0.95	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-171863555;