1-168191428-G-T

Position:

• chr1-168191428-G-T

Variant summary

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

The NM_152902.5(TIPRL):​c.444G>T​(p.Lys148Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000725 in 1,379,902 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: 7.2e-7 (0 hom.)
• Consequence: TIPRL NM_152902.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.21

Genes affected

TIPRL (HGNC:30231): (TOR signaling pathway regulator) TIPRL is an inhibitory regulator of protein phosphatase-2A (PP2A) (see PPP2CA; MIM 176915), PP4 (see PPP4C; MIM 602035), and PP6 (see PPP6C; MIM 612725) (McConnell et al., 2007 [PubMed 17384681]).[supplied by OMIM, Nov 2010]

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=0.34731755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIPRL	NM_152902.5	c.444G>T	p.Lys148Asn	missense_variant	4/7	ENST00000367833.7	NP_690866.1
TIPRL	NM_001031800.3	c.444G>T	p.Lys148Asn	missense_variant	4/5		NP_001026970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIPRL	ENST00000367833.7	c.444G>T	p.Lys148Asn	missense_variant	4/7	1	NM_152902.5	ENSP00000356807	P1
TIPRL	ENST00000367830.3	c.444G>T	p.Lys148Asn	missense_variant	4/5	1		ENSP00000356804

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.25e-7 AC: 1 AN: 1379902 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 684898

Gnomad4 AFR exome AF: 0.0000356

Gnomad4 AMR exome AF: 0.00

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2024

The c.444G>T (p.K148N) alteration is located in exon 4 (coding exon 4) of the TIPRL gene. This alteration results from a G to T substitution at nucleotide position 444, causing the lysine (K) at amino acid position 148 to be replaced by an asparagine (N). 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	Uncertain	0.51
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.061	T;.
Eigen	Benign	-0.033
Eigen_PC	Benign	0.0038
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.26
Sift	Benign	0.22	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.59	P;P
Vest4		0.40
MutPred		0.56		Loss of methylation at K148 (P = 0.0025);Loss of methylation at K148 (P = 0.0025);
MVP		0.068
MPC		0.85
ClinPred		0.90	D
GERP RS		0.44
Varity_R		0.39
gMVP		0.54

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: rs759992722; hg19: chr1-168160666;