chr19-38256231-C-G

Variant names:

• chr19-38256231-C-G
• rs1166839796
• NM_033256.3:c.109G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033256.3(PPP1R14A):​c.109G>C​(p.Val37Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000357 in 1,400,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: PPP1R14A NM_033256.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.17

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.289764).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R14A	NM_033256.3	c.109G>C	p.Val37Leu	missense_variant	Exon 1 of 4	ENST00000301242.9	NP_150281.1
PPP1R14A	NM_001243947.2	c.109G>C	p.Val37Leu	missense_variant	Exon 1 of 3		NP_001230876.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R14A	ENST00000301242.9	c.109G>C	p.Val37Leu	missense_variant	Exon 1 of 4	1	NM_033256.3	ENSP00000301242.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000652 AC: 1 AN: 153342 Hom.: 0 AF XY: 0.0000120 AC XY: 1 AN XY: 83492

Gnomad AFR exome AF: 0.000117

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1400350 Hom.: 0 Cov.: 31 AF XY: 0.00000289 AC XY: 2 AN XY: 692294

Gnomad4 AFR exome AF: 0.000155

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 Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Benign	0.038	T;.;T;.
Eigen	Benign	0.10
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	.;L;L;.
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.3	.;N;N;.
REVEL	Uncertain	0.46
Sift	Benign	0.38	.;T;T;.
Sift4G	Benign	0.088	T;T;T;T
Polyphen		0.98, 0.98	.;D;D;.
Vest4		0.46
MutPred		0.74		Loss of methylation at K40 (P = 0.0665);Loss of methylation at K40 (P = 0.0665);Loss of methylation at K40 (P = 0.0665);Loss of methylation at K40 (P = 0.0665);
MVP		0.085
MPC		2.7
ClinPred		0.42	T
GERP RS		3.4
Varity_R		0.26
gMVP		0.75

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: rs1166839796; hg19: chr19-38746871;