19-38251388-C-G

Variant names:

• chr19-38251388-C-G
• rs201166412
• NM_033256.3:c.374G>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_033256.3(PPP1R14A):​c.374G>C​(p.Arg125Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000056 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PPP1R14A NM_033256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.99

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014341652).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R14A	NM_033256.3	c.374G>C	p.Arg125Pro	missense_variant	Exon 4 of 4	ENST00000301242.9	NP_150281.1
PPP1R14A	NM_001243947.2	c.293G>C	p.Arg98Pro	missense_variant	Exon 3 of 3		NP_001230876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R14A	ENST00000301242.9	c.374G>C	p.Arg125Pro	missense_variant	Exon 4 of 4	1	NM_033256.3	ENSP00000301242.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000564 AC: 79 AN: 1401304 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 47 AN XY: 697198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000186

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000342

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000942

Gnomad4 NFE exome AF: 0.0000128

Gnomad4 OTH exome AF: 0.0000519

GnomAD4 genome Cov.: 31

ExAC AF: 0.000745 AC: 90

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.5
DANN	Benign	0.79
DEOGEN2	Benign	0.011	T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	.;.;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.29	.;N;N
REVEL	Benign	0.015
Sift	Benign	0.24	.;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0, 0.0010	.;B;B
Vest4		0.15
MVP		0.10
MPC		0.0043
ClinPred		0.0033	T
GERP RS		-6.4
Varity_R		0.23
gMVP		0.12

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

Other links and lift over

dbSNP: rs201166412; hg19: chr19-38742028;