19-38251388-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033256.3(PPP1R14A):c.374G>T(p.Arg125Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000386 in 1,553,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

PPP1R14A
NM_033256.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.99

Variant links:

Genes affected

PPP1R14A (HGNC:14871): (protein phosphatase 1 regulatory inhibitor subunit 14A) The protein encoded by this gene belongs to the protein phosphatase 1 (PP1) inhibitor family. This protein is an inhibitor of smooth muscle myosin phosphatase, and has higher inhibitory activity when phosphorylated. Inhibition of myosin phosphatase leads to increased myosin phosphorylation and enhanced smooth muscle contraction. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Sep 2011]

PPP1R14A links:

SPINT2 (HGNC:11247): (serine peptidase inhibitor, Kunitz type 2) This gene encodes a transmembrane protein with two extracellular Kunitz domains that inhibits a variety of serine proteases. The protein inhibits HGF activator which prevents the formation of active hepatocyte growth factor. This gene is a putative tumor suppressor, and mutations in this gene result in congenital sodium diarrhea. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

SPINT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.07609144).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1R14A	NM_033256.3 linkuse as main transcript	c.374G>T	p.Arg125Leu	missense_variant	4/4	ENST00000301242.9
PPP1R14A	NM_001243947.2 linkuse as main transcript	c.293G>T	p.Arg98Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1R14A	ENST00000301242.9 linkuse as main transcript	c.374G>T	p.Arg125Leu	missense_variant	4/4	1	NM_033256.3	P1	Q96A00-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1401360

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697230

show subpopulations

Gnomad4 AFR exome

AF:

0.0000339

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152010

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000302

ExAC

AF:

0.00000828

AC:

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 20, 2023

The c.374G>T (p.R125L) alteration is located in exon 4 (coding exon 4) of the PPP1R14A gene. This alteration results from a G to T substitution at nucleotide position 374, causing the arginine (R) at amino acid position 125 to be replaced by a leucine (L). 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

0.096

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

Cadd

Benign

7.9

Dann

Benign

0.96

DEOGEN2

Benign

0.033

T;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.79

T;T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.076

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.28

Sift4G

Benign

0.17

T;T;T

Polyphen

0.15, 0.36

.;B;B

Vest4

0.18

MutPred

0.48

.;.;Gain of glycosylation at S128 (P = 0.0863);

MVP

0.12

MPC

0.0048

ClinPred

0.057

GERP RS

-6.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.095

gMVP

0.13

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