19-48875737-A-G

Position:

• chr19-48875737-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014330.5(PPP1R15A):​c.1789A>G​(p.Thr597Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 1,613,168 control chromosomes in the GnomAD database, including 73,476 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.35 (10630 hom., cov: 31)
  • Exomes 𝑓: 0.29 (62846 hom.)
• Consequence: PPP1R15A NM_014330.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32

Genes affected

PPP1R15A (HGNC:14375): (protein phosphatase 1 regulatory subunit 15A) This gene is a member of a group of genes whose transcript levels are increased following stressful growth arrest conditions and treatment with DNA-damaging agents. The induction of this gene by ionizing radiation occurs in certain cell lines regardless of p53 status, and its protein response is correlated with apoptosis following ionizing radiation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.902102E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPP1R15A	NM_014330.5	c.1789A>G	p.Thr597Ala	missense_variant	3/3	ENST00000200453.6	NP_055145.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPP1R15A	ENST00000200453.6	c.1789A>G	p.Thr597Ala	missense_variant	3/3	1	NM_014330.5	ENSP00000200453.4
PPP1R15A	ENST00000704027.1	c.1837A>G	p.Thr613Ala	missense_variant	2/2			ENSP00000515637.1
PPP1R15A	ENST00000704026.1	c.1504A>G	p.Thr502Ala	missense_variant	4/4			ENSP00000515636.1
PPP1R15A	ENST00000600406.2	c.*644A>G		3_prime_UTR_variant	2/2	6		ENSP00000469239.2

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53775 AN: 151748 Hom.: 10616 Cov.: 31

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.299

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.352

GnomAD3 exomes AF: 0.294 AC: 73171 AN: 248556 Hom.: 11471 AF XY: 0.294 AC XY: 39544 AN XY: 134580

Gnomad AFR exome AF: 0.541

Gnomad AMR exome AF: 0.258

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.178

Gnomad SAS exome AF: 0.327

Gnomad FIN exome AF: 0.312

Gnomad NFE exome AF: 0.275

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.288 AC: 420657 AN: 1461302 Hom.: 62846 Cov.: 38 AF XY: 0.289 AC XY: 209816 AN XY: 726970

Gnomad4 AFR exome AF: 0.556

Gnomad4 AMR exome AF: 0.267

Gnomad4 ASJ exome AF: 0.325

Gnomad4 EAS exome AF: 0.257

Gnomad4 SAS exome AF: 0.330

Gnomad4 FIN exome AF: 0.311

Gnomad4 NFE exome AF: 0.276

Gnomad4 OTH exome AF: 0.302

GnomAD4 genome AF: 0.355 AC: 53847 AN: 151866 Hom.: 10630 Cov.: 31 AF XY: 0.354 AC XY: 26263 AN XY: 74220

Gnomad4 AFR AF: 0.538

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.334

Gnomad4 EAS AF: 0.197

Gnomad4 SAS AF: 0.329

Gnomad4 FIN AF: 0.299

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.351

Alfa AF: 0.287 Hom.: 12304

Bravo AF: 0.359

TwinsUK AF: 0.259 AC: 961

ALSPAC AF: 0.283 AC: 1091

ESP6500AA AF: 0.525 AC: 2312

ESP6500EA AF: 0.287 AC: 2469

ExAC AF: 0.298 AC: 36140

Asia WGS AF: 0.275 AC: 955 AN: 3478

EpiCase AF: 0.281

EpiControl AF: 0.279

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.7
DANN	Benign	0.50
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0043	N
LIST_S2	Benign	0.10	T
MetaRNN	Benign	0.000039	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.8	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.058
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.020
MPC		0.080
ClinPred		0.00011	T
GERP RS		2.8
Varity_R		0.028
gMVP		0.15

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: rs500079; hg19: chr19-49378994; COSMIC: COSV52338351;