1-168179168-G-A

Position:

• chr1-168179168-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000367833.7(TIPRL):​c.91G>A​(p.Ala31Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,732 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: 0.0000027 (0 hom.)
• Consequence: TIPRL ENST00000367833.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.63

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13330457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIPRL	NM_152902.5	c.91G>A	p.Ala31Thr	missense_variant	1/7	ENST00000367833.7	NP_690866.1
TIPRL	NM_001031800.3	c.91G>A	p.Ala31Thr	missense_variant	1/5		NP_001026970.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIPRL	ENST00000367833.7	c.91G>A	p.Ala31Thr	missense_variant	1/7	1	NM_152902.5	ENSP00000356807.2
TIPRL	ENST00000367830.3	c.91G>A	p.Ala31Thr	missense_variant	1/5	1		ENSP00000356804.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461732 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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 12, 2024

The c.91G>A (p.A31T) alteration is located in exon 1 (coding exon 1) of the TIPRL gene. This alteration results from a G to A substitution at nucleotide position 91, causing the alanine (A) at amino acid position 31 to be replaced by a threonine (T). 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	0.094
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0099	T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.85	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.049
Sift	Benign	0.32	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.15	B;B
Vest4		0.22
MutPred		0.24		Gain of phosphorylation at A31 (P = 0.0404);Gain of phosphorylation at A31 (P = 0.0404);
MVP		0.093
MPC		0.64
ClinPred		0.81	D
GERP RS		4.5
Varity_R		0.16
gMVP		0.41

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: rs371476972; hg19: chr1-168148406;