rs1225947843

Variant names:

• chr19-45382610-G-A
• rs1225947843
• NM_006663.4:c.2365C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006663.4(PPP1R13L):​c.2365C>T​(p.Arg789Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,316 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PPP1R13L NM_006663.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78

Genes affected

PPP1R13L (HGNC:18838): (protein phosphatase 1 regulatory subunit 13 like) IASPP is one of the most evolutionarily conserved inhibitors of p53 (TP53; MIM 191170), whereas ASPP1 (MIM 606455) and ASPP2 (MIM 602143) are activators of p53.[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R13L	NM_006663.4	c.2365C>T	p.Arg789Trp	missense_variant	Exon 12 of 13	ENST00000360957.10	NP_006654.2
PPP1R13L	NM_001142502.2	c.2365C>T	p.Arg789Trp	missense_variant	Exon 12 of 13		NP_001135974.1
PPP1R13L	XM_017026177.2	c.2365C>T	p.Arg789Trp	missense_variant	Exon 13 of 14		XP_016881666.1
PPP1R13L	XM_017026178.2	c.2365C>T	p.Arg789Trp	missense_variant	Exon 13 of 14		XP_016881667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R13L	ENST00000360957.10	c.2365C>T	p.Arg789Trp	missense_variant	Exon 12 of 13	1	NM_006663.4	ENSP00000354218.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461316 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726990

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Nov 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2365C>T (p.R789W) alteration is located in exon 12 (coding exon 11) of the PPP1R13L gene. This alteration results from a C to T substitution at nucleotide position 2365, causing the arginine (R) at amino acid position 789 to be replaced by a tryptophan (W). 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.2	M;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.54		Loss of disorder (P = 0.0043);Loss of disorder (P = 0.0043);
MVP		0.78
MPC		1.1
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.80
gMVP		0.82

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: rs1225947843; hg19: chr19-45885868;