12-79788661-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002480.3(PPP1R12A):c.2789C>G(p.Thr930Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP1R12A NM_002480.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25

Genes affected

PPP1R12A (HGNC:7618): (protein phosphatase 1 regulatory subunit 12A) Myosin phosphatase target subunit 1, which is also called the myosin-binding subunit of myosin phosphatase, is one of the subunits of myosin phosphatase. Myosin phosphatase regulates the interaction of actin and myosin downstream of the guanosine triphosphatase Rho. The small guanosine triphosphatase Rho is implicated in myosin light chain (MLC) phosphorylation, which results in contraction of smooth muscle and interaction of actin and myosin in nonmuscle cells. The guanosine triphosphate (GTP)-bound, active form of RhoA (GTP.RhoA) specifically interacted with the myosin-binding subunit (MBS) of myosin phosphatase, which regulates the extent of phosphorylation of MLC. Rho-associated kinase (Rho-kinase), which is activated by GTP. RhoA, phosphorylated MBS and consequently inactivated myosin phosphatase. Overexpression of RhoA or activated RhoA in NIH 3T3 cells increased phosphorylation of MBS and MLC. Thus, Rho appears to inhibit myosin phosphatase through the action of Rho-kinase. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2009]

ACMG classification

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=0.25845534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPP1R12A	NM_002480.3	c.2789C>G	p.Thr930Ser	missense_variant	21/25	ENST00000450142.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPP1R12A	ENST00000450142.7	c.2789C>G	p.Thr930Ser	missense_variant	21/25	1	NM_002480.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Genitourinary and/or brain malformation syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 27, 2020

The PPP1R12A c.2789C>G (p.Thr930Ser) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were identified through this search. This variant is not found in the Genome Aggregation Database in a region of good sequence coverage, suggesting it is rare. To date, all reported pathogenic variants in the PPP1R12A gene have been predicted null variants, and the majority were proven de novo (Hughes et al. 2020). Based on the limited evidence available, the p.Thr930Ser variant is classified as a variant of uncertain significance for genitourinary and/or brain malformation syndrome. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.15	T;T;.;T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.54	T;.;T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N;N;N;.;N;N
REVEL	Benign	0.13
Sift	Benign	0.10	T;T;T;.;T;D
Sift4G	Benign	0.42	T;T;T;T;T;T
Polyphen		0.0	B;B;B;.;.;P
Vest4		0.28
MutPred		0.11		Loss of methylation at K926 (P = 0.165);Loss of methylation at K926 (P = 0.165);Loss of methylation at K926 (P = 0.165);.;.;.;
MVP		0.51
MPC		0.12
ClinPred		0.83	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.087

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: rs1871411076; hg19: chr12-80182441;