12-79775976-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_002480.3(PPP1R12A):​c.3046G>A​(p.Asp1016Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

PPP1R12A
NM_002480.3 missense

Scores

8
6
5

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.22
Variant links:
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]
PPP1R12A-AS2 (HGNC:55456): (PPP1R12A antisense RNA 2)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 12-79775976-C-T is Pathogenic according to our data. Variant chr12-79775976-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1309399.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PPP1R12ANM_002480.3 linkc.3046G>A p.Asp1016Asn missense_variant Exon 25 of 25 ENST00000450142.7 NP_002471.1 O14974-1B2RAH5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PPP1R12AENST00000450142.7 linkc.3046G>A p.Asp1016Asn missense_variant Exon 25 of 25 1 NM_002480.3 ENSP00000389168.2 O14974-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
May 23, 2024
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Benign
-0.088
T
BayesDel_noAF
Benign
-0.36
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.63
D;D;.;.;.
Eigen
Pathogenic
0.69
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;.;D;D;D
M_CAP
Benign
0.024
T
MetaRNN
Uncertain
0.61
D;D;D;D;D
MetaSVM
Benign
-0.38
T
MutationAssessor
Pathogenic
2.9
M;M;.;.;.
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-3.4
D;D;D;D;D
REVEL
Uncertain
0.32
Sift
Uncertain
0.0060
D;D;D;D;D
Sift4G
Uncertain
0.0070
D;D;D;D;D
Polyphen
0.99
D;D;D;.;B
Vest4
0.72
MutPred
0.19
Gain of helix (P = 0.0082);Gain of helix (P = 0.0082);.;.;.;
MVP
0.53
MPC
0.23
ClinPred
0.97
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.34
gMVP
0.16

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-80169756; API