8-10765626-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_017884.6(PINX1):c.762C>A(p.Ser254Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,461,454 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 Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S254C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

PINX1
NM_017884.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.778

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]

PINX1 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030176014).

BP6

Variant 8-10765626-G-T is Benign according to our data. Variant chr8-10765626-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3213123.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PINX1	NM_017884.6 linkuse as main transcript	c.762C>A	p.Ser254Arg	missense_variant	7/7	ENST00000314787.8
LOC102723313	NR_146188.1 linkuse as main transcript	n.341-2774G>T		intron_variant, non_coding_transcript_variant
PINX1	NM_001284356.2 linkuse as main transcript	c.*160C>A		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PINX1	ENST00000314787.8 linkuse as main transcript	c.762C>A	p.Ser254Arg	missense_variant	7/7	1	NM_017884.6	P2	Q96BK5-1
	ENST00000657150.1 linkuse as main transcript	n.174-2774G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000804

AC:

AN:

248776

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134984

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461454

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000378

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000287

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.82

Cadd

Benign

0.014

Dann

Benign

0.64

DEOGEN2

Benign

0.014

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0018

LIST_S2

Benign

0.32

M_CAP

Benign

0.0015

MetaRNN

Benign

0.030

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.4

MutationTaster

Benign

1.0

N;N;N;N

PROVEAN

Benign

1.1

REVEL

Benign

0.021

Sift

Benign

0.87

Sift4G

Benign

0.92

Polyphen

0.0010

Vest4

0.079

MutPred

0.13

Gain of helix (P = 0.0117);

MVP

0.17

MPC

0.0012

ClinPred

0.028

GERP RS

-1.3

Varity_R

0.052

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over