chr20-59939171-T-C

Variant names:

• chr20-59939171-T-C
• NM_006242.4:c.761A>G

Variant summary

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

The NM_006242.4(PPP1R3D):​c.761A>G​(p.His254Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PPP1R3D NM_006242.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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

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=0.3691361).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R3D	NM_006242.4	c.761A>G	p.His254Arg	missense_variant	Exon 1 of 1	ENST00000370996.5	NP_006233.1
FAM217B	NM_001190826.2	c.-203+1059T>C		intron_variant	Intron 2 of 4		NP_001177755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R3D	ENST00000370996.5	c.761A>G	p.His254Arg	missense_variant	Exon 1 of 1	6	NM_006242.4	ENSP00000360035.3
FAM217B	ENST00000358293.7	c.-203+1059T>C		intron_variant	Intron 2 of 4	2		ENSP00000351040.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457948 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 724592

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.761A>G (p.H254R) alteration is located in exon 1 (coding exon 1) of the PPP1R3D gene. This alteration results from a A to G substitution at nucleotide position 761, causing the histidine (H) at amino acid position 254 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.0032	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.061	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.25
Sift	Benign	0.18	T
Sift4G	Benign	0.34	T
Polyphen		0.38	B
Vest4		0.36
MutPred		0.65		Gain of MoRF binding (P = 0.0559);
MVP		0.82
MPC		1.2
ClinPred		0.88	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.56

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: chr20-58514226;