19-48875737-A-G

Variant names:

• chr19-48875737-A-G
• rs500079
• NM_014330.5:c.1789A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 36 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014330.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R15A	NM_014330.5	MANE Select	c.1789A>G	p.Thr597Ala	missense	Exon 3 of 3	NP_055145.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPP1R15A	ENST00000200453.6	TSL:1 MANE Select	c.1789A>G	p.Thr597Ala	missense	Exon 3 of 3	ENSP00000200453.4
	PPP1R15A	ENST00000704027.1		c.1837A>G	p.Thr613Ala	missense	Exon 2 of 2	ENSP00000515637.1
	PPP1R15A	ENST00000704026.1		c.1504A>G	p.Thr502Ala	missense	Exon 4 of 4	ENSP00000515636.1

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

GnomAD2 exomes AF: 0.294 AC: 73171 AN: 248556 AF XY: 0.294

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 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

African (AFR) AF: 0.556 AC: 18627 AN: 33474

American (AMR) AF: 0.267 AC: 11924 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 8488 AN: 26112

East Asian (EAS) AF: 0.257 AC: 10181 AN: 39692

South Asian (SAS) AF: 0.330 AC: 28455 AN: 86234

European-Finnish (FIN) AF: 0.311 AC: 16528 AN: 53210

Middle Eastern (MID) AF: 0.317 AC: 1824 AN: 5762

European-Non Finnish (NFE) AF: 0.276 AC: 306376 AN: 1111756

Other (OTH) AF: 0.302 AC: 18254 AN: 60358

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

African (AFR) AF: 0.538 AC: 22298 AN: 41416

American (AMR) AF: 0.303 AC: 4622 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1159 AN: 3466

East Asian (EAS) AF: 0.197 AC: 1005 AN: 5110

South Asian (SAS) AF: 0.329 AC: 1585 AN: 4812

European-Finnish (FIN) AF: 0.299 AC: 3165 AN: 10574

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18870 AN: 67896

Other (OTH) AF: 0.351 AC: 741 AN: 2114

Alfa AF: 0.291 Hom.: 18100

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 v4.9

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
PhyloP100		1.3
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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