20-59939204-G-C

Variant names:

• chr20-59939204-G-C
• rs753780608
• NM_006242.4:c.728C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006242.4(PPP1R3D):​c.728C>G​(p.Pro243Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000679 in 1,457,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: PPP1R3D NM_006242.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.76
• Publications: 0 publications found

Genes affected

PPP1R3D (HGNC:9294): (protein phosphatase 1 regulatory subunit 3D) Phosphorylation of serine and threonine residues in proteins is a crucial step in the regulation of many cellular functions ranging from hormonal regulation to cell division and even short-term memory. The level of phosphorylation is controlled by the opposing actions of protein kinases and protein phosphatases. Protein phosphatase 1 (PP1) is 1 of 4 major serine/threonine-specific protein phosphatases which have been identified in eukaryotic cells. PP1 associates with various regulatory subunits that dictate its subcellular localization and modulate its substrate specificity. Several subunits that target PP1 to glycogen have been identified. This gene encodes a glycogen-targeting subunit of PP1. [provided by RefSeq, Jul 2008]

FAM217B (HGNC:16170): (family with sequence similarity 217 member B) Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006242.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R3D	NM_006242.4	MANE Select	c.728C>G	p.Pro243Arg	missense	Exon 1 of 1	NP_006233.1	O95685
	FAM217B	NM_001190826.2		c.-203+1092G>C		intron	N/A	NP_001177755.1	Q9NTX9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R3D	ENST00000370996.5	TSL:6 MANE Select	c.728C>G	p.Pro243Arg	missense	Exon 1 of 1	ENSP00000360035.3	O95685
	FAM217B	ENST00000358293.7	TSL:2	c.-203+1092G>C		intron	N/A	ENSP00000351040.3	Q9NTX9
	FAM217B	ENST00000890684.1		c.-203+1092G>C		intron	N/A	ENSP00000560743.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248912 AF XY: 0.0000222

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000679 AC: 99 AN: 1457620 Hom.: 0 Cov.: 31 AF XY: 0.0000635 AC XY: 46 AN XY: 724388

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52648

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000874 AC: 97 AN: 1109328

Other (OTH) AF: 0.0000332 AC: 2 AN: 60194

GnomAD4 genome Cov.: 33

Alfa AF: 0.000125 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.0085	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.69		Loss of catalytic residue at P243 (P = 0.0355)
MVP		0.88
MPC		2.0
ClinPred		0.98	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.64
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs753780608; hg19: chr20-58514259;