NM_006663.4:c.2241C>G

Variant names:

• chr19-45385569-G-C
• rs1114167453
• NM_006663.4:c.2241C>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_006663.4(PPP1R13L):​c.2241C>G​(p.Tyr747*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPP1R13L NM_006663.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.789
• Publications: 3 publications found

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]

PPP1R13L Gene-Disease associations (from GenCC):

• arrhythmogenic cardiomyopathy with variable ectodermal abnormalities

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• dilated cardiomyopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-45385569-G-C is Pathogenic according to our data. Variant chr19-45385569-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 427813.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPP1R13L	NM_006663.4	c.2241C>G	p.Tyr747*	stop_gained	Exon 11 of 13	ENST00000360957.10	NP_006654.2
PPP1R13L	NM_001142502.2	c.2241C>G	p.Tyr747*	stop_gained	Exon 11 of 13		NP_001135974.1
PPP1R13L	XM_017026177.2	c.2241C>G	p.Tyr747*	stop_gained	Exon 12 of 14		XP_016881666.1
PPP1R13L	XM_017026178.2	c.2241C>G	p.Tyr747*	stop_gained	Exon 12 of 14		XP_016881667.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPP1R13L	ENST00000360957.10	c.2241C>G	p.Tyr747*	stop_gained	Exon 11 of 13	1	NM_006663.4	ENSP00000354218.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Cardio-cutaneous syndrome Pathogenic:1

-

Molecular Laboratory of the Institute of Human Genetics, Galilee Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Arrhythmogenic cardiomyopathy with variable ectodermal abnormalities Pathogenic:1

Sep 26, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		0.79
Vest4		0.88
GERP RS		3.3
PromoterAI		0.070	Neutral
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1114167453; hg19: chr19-45888827;