Variant 6-36963126-A-G details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_153370.3(PI16):c.784A>G(p.Thr262Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000876 in 1,614,010 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00091 ( 1 hom. )

Consequence

PI16
NM_153370.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.990

Variant links:

Genes affected

PI16 (HGNC:21245): (peptidase inhibitor 16) Predicted to enable peptidase inhibitor activity. Predicted to be involved in negative regulation of peptidase activity. Predicted to act upstream of or within negative regulation of cell growth involved in cardiac muscle cell development. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

PI16 links:

PI16 (HGNC:):

PI16 links:

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=0.020640373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PI16	NM_153370.3 linkuse as main transcript	c.784A>G	p.Thr262Ala	missense_variant	5/7	ENST00000373674.4	NP_699201.2	Q6UXB8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PI16	ENST00000373674.4 linkuse as main transcript	c.784A>G	p.Thr262Ala	missense_variant	5/7	1	NM_153370.3	ENSP00000362778.3	Q6UXB8-1
PI16	ENST00000611814.4 linkuse as main transcript	c.784A>G	p.Thr262Ala	missense_variant	6/8	5		ENSP00000478888.1	Q6UXB8-1
PI16	ENST00000647861.1 linkuse as main transcript	c.784A>G	p.Thr262Ala	missense_variant	7/9			ENSP00000497550.1	Q6UXB8-1
PI16	ENST00000491324.1 linkuse as main transcript	n.44+93A>G		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000559

AC:

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000569

AC:

143

AN:

251474

Hom.:

AF XY:

0.000522

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000686

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000941

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000909

AC:

1329

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000840

AC XY:

611

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000881

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.000944

GnomAD4 genome

AF:

0.000559

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.000471

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00110

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000917

Hom.:

Bravo

AF:

0.000442

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000593

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000948

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 submitter

clinical testing

Ambry Genetics

Jan 16, 2024

The c.784A>G (p.T262A) alteration is located in exon 5 (coding exon 5) of the PI16 gene. This alteration results from a A to G substitution at nucleotide position 784, causing the threonine (T) at amino acid position 262 to be replaced by an alanine (A). 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

0.088

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0095

T;T;T

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.60

.;T;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;L

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

.;.;N

REVEL

Benign

0.060

Sift

Uncertain

0.0020

.;.;D

Sift4G

Uncertain

0.0090

.;D;D

Polyphen

0.42

B;B;B

Vest4

0.11, 0.11

MVP

0.33

MPC

0.45

ClinPred

0.063

GERP RS

3.4

Varity_R

0.13

gMVP

0.30

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