8-10765625-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_017884.6(PINX1):​c.763G>A​(p.Ala255Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

PINX1
NM_017884.6 missense

Scores

18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0580
Variant links:
Genes affected
PINX1 (HGNC:30046): (PIN2 (TERF1) interacting telomerase inhibitor 1) Enables telomerase RNA binding activity and telomerase inhibitor activity. Involved in several processes, including negative regulation of DNA biosynthetic process; positive regulation of protein localization to nucleolus; and protein localization to organelle. Acts upstream of or within telomere maintenance via telomerase. Located in several cellular components, including chromosomal region; nuclear lumen; and spindle. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.014366746).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PINX1NM_017884.6 linkuse as main transcriptc.763G>A p.Ala255Thr missense_variant 7/7 ENST00000314787.8 NP_060354.4
LOC102723313NR_146188.1 linkuse as main transcriptn.341-2775C>T intron_variant, non_coding_transcript_variant
PINX1NM_001284356.2 linkuse as main transcriptc.*161G>A 3_prime_UTR_variant 6/6 NP_001271285.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PINX1ENST00000314787.8 linkuse as main transcriptc.763G>A p.Ala255Thr missense_variant 7/71 NM_017884.6 ENSP00000318966 P2Q96BK5-1
ENST00000657150.1 linkuse as main transcriptn.174-2775C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.000184
AC:
28
AN:
152192
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000651
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000482
AC:
12
AN:
248812
Hom.:
0
AF XY:
0.0000370
AC XY:
5
AN XY:
135004
show subpopulations
Gnomad AFR exome
AF:
0.000646
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000274
AC:
40
AN:
1461532
Hom.:
0
Cov.:
32
AF XY:
0.0000289
AC XY:
21
AN XY:
727068
show subpopulations
Gnomad4 AFR exome
AF:
0.000538
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000184
AC:
28
AN:
152192
Hom.:
0
Cov.:
33
AF XY:
0.000188
AC XY:
14
AN XY:
74346
show subpopulations
Gnomad4 AFR
AF:
0.000651
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000585
Hom.:
0
Bravo
AF:
0.000174
ESP6500AA
AF:
0.00103
AC:
4
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000579
AC:
7

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 GeneticsFeb 23, 2023The c.763G>A (p.A255T) alteration is located in exon 7 (coding exon 7) of the PINX1 gene. This alteration results from a G to A substitution at nucleotide position 763, causing the alanine (A) at amino acid position 255 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
0.070
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.82
CADD
Benign
4.6
DANN
Benign
0.93
DEOGEN2
Benign
0.025
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.27
T
M_CAP
Benign
0.0044
T
MetaRNN
Benign
0.014
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
L
MutationTaster
Benign
1.0
N;N;N;N
PROVEAN
Benign
0.52
N
REVEL
Benign
0.021
Sift
Benign
0.21
T
Sift4G
Benign
0.57
T
Polyphen
0.0
B
Vest4
0.040
MVP
0.45
MPC
0.0014
ClinPred
0.0098
T
GERP RS
-1.4
Varity_R
0.018
gMVP
0.015

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

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

Other links and lift over

dbSNP: rs202202690; hg19: chr8-10623135; COSMIC: COSV59108796; COSMIC: COSV59108796; API