15-66337167-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_017858.3(TIPIN):ā€‹c.697A>Cā€‹(p.Thr233Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,312 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

TIPIN
NM_017858.3 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.611
Variant links:
Genes affected
TIPIN (HGNC:30750): (TIMELESS interacting protein) The protein encoded by this gene is part of the replisome complex, a group of proteins that support DNA replication. It binds TIM, which is involved in circadian rhythm regulation, and aids in protecting cells against DNA damage and stress. Two pseudogenes and two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a modified_residue Phosphothreonine (size 0) in uniprot entity TIPIN_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.096922785).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TIPINNM_017858.3 linkuse as main transcriptc.697A>C p.Thr233Pro missense_variant 8/8 ENST00000261881.9 NP_060328.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TIPINENST00000261881.9 linkuse as main transcriptc.697A>C p.Thr233Pro missense_variant 8/81 NM_017858.3 ENSP00000261881 P1
TIPINENST00000562124.5 linkuse as main transcriptc.697A>C p.Thr233Pro missense_variant 8/85 ENSP00000457406
TIPINENST00000566524.5 linkuse as main transcriptc.*396A>C 3_prime_UTR_variant, NMD_transcript_variant 7/72 ENSP00000455656

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250908
Hom.:
0
AF XY:
0.00000737
AC XY:
1
AN XY:
135660
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461166
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726856
show subpopulations
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 24, 2023The c.697A>C (p.T233P) alteration is located in exon 8 (coding exon 7) of the TIPIN gene. This alteration results from a A to C substitution at nucleotide position 697, causing the threonine (T) at amino acid position 233 to be replaced by a proline (P). 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
0.083
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
11
DANN
Benign
0.60
DEOGEN2
Benign
0.013
T;.
Eigen
Benign
-0.72
Eigen_PC
Benign
-0.88
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.54
T;T
M_CAP
Benign
0.0044
T
MetaRNN
Benign
0.097
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.9
L;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.69
N;N
REVEL
Benign
0.094
Sift
Benign
0.032
D;D
Sift4G
Benign
0.25
T;.
Polyphen
0.84
P;.
Vest4
0.19
MutPred
0.14
Gain of catalytic residue at T233 (P = 0.0237);Gain of catalytic residue at T233 (P = 0.0237);
MVP
0.25
MPC
0.25
ClinPred
0.082
T
GERP RS
-0.52
Varity_R
0.079
gMVP
0.075

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1360379047; hg19: chr15-66629505; API