11-799816-G-C

Variant names:

• chr11-799816-G-C
• rs1385272293
• NM_145886.4:c.2473C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_145886.4(PIDD1):​c.2473C>G​(p.Arg825Gly) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R825W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PIDD1 NM_145886.4 missense, splice_region
• Scores: Splicing: ADA: 0.001669
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56
• Publications: 0 publications found

Genes affected

PIDD1 (HGNC:16491): (p53-induced death domain protein 1) The protein encoded by this gene contains a leucine-rich repeat and a death domain. This protein has been shown to interact with other death domain proteins, such as Fas (TNFRSF6)-associated via death domain (FADD) and MAP-kinase activating death domain-containing protein (MADD), and thus may function as an adaptor protein in cell death-related signaling processes. The expression of the mouse counterpart of this gene has been found to be positively regulated by the tumor suppressor p53 and to induce cell apoptosis in response to DNA damage, which suggests a role for this gene as an effector of p53-dependent apoptosis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

RPLP2 (HGNC:10377): (ribosomal protein lateral stalk subunit P2) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal phosphoprotein that is a component of the 60S subunit. The protein, which is a functional equivalent of the E. coli L7/L12 ribosomal protein, belongs to the L12P family of ribosomal proteins. It plays an important role in the elongation step of protein synthesis. Unlike most ribosomal proteins, which are basic, the encoded protein is acidic. Its C-terminal end is nearly identical to the C-terminal ends of the ribosomal phosphoproteins P0 and P1. The P2 protein can interact with P0 and P1 to form a pentameric complex consisting of P1 and P2 dimers, and a P0 monomer. The protein is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145886.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIDD1	NM_145886.4	MANE Select	c.2473C>G	p.Arg825Gly	missense splice_region	Exon 15 of 16	NP_665893.2	Q9HB75-1
	PIDD1	NM_145887.4		c.2422C>G	p.Arg808Gly	missense splice_region	Exon 15 of 16	NP_665894.2	Q9HB75-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIDD1	ENST00000347755.10	TSL:1 MANE Select	c.2473C>G	p.Arg825Gly	missense splice_region	Exon 15 of 16	ENSP00000337797.5	Q9HB75-1
	PIDD1	ENST00000411829.6	TSL:1	c.2422C>G	p.Arg808Gly	missense splice_region	Exon 14 of 15	ENSP00000416801.2	Q9HB75-2
	PIDD1	ENST00000525028.6	TSL:1	n.*2173C>G		splice_region non_coding_transcript_exon	Exon 14 of 15	ENSP00000436342.1	E9PPT6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	0.14
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.63
Sift	Benign	0.030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.55		Gain of loop (P = 0.069)
MVP		0.81
MPC		0.30
ClinPred		0.98	D
GERP RS		0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.59
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.010		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: rs1385272293; hg19: chr11-799816;