11-799386-C-T

Variant names:

• chr11-799386-C-T
• rs373561275
• NM_145886.4:c.2654G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_145886.4(PIDD1):​c.2654G>A​(p.Arg885Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000405 in 1,611,900 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (8 hom.)
• Consequence: PIDD1 NM_145886.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0790
• Publications: 5 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]

PANO1 (HGNC:51237): (proapoptotic nucleolar protein 1) Involved in negative regulation of proteasomal ubiquitin-dependent protein catabolic process; positive regulation of apoptotic process; and regulation of protein stability. Located in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045231283).
• BP6: Variant 11-799386-C-T is Benign according to our data. Variant chr11-799386-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2590319.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000236 (36/152350) while in subpopulation SAS AF = 0.00683 (33/4834). AF 95% confidence interval is 0.005. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

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.2654G>A	p.Arg885Gln	missense	Exon 16 of 16	NP_665893.2	Q9HB75-1
	PIDD1	NM_145887.4		c.2603G>A	p.Arg868Gln	missense	Exon 16 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.2654G>A	p.Arg885Gln	missense	Exon 16 of 16	ENSP00000337797.5	Q9HB75-1
	PIDD1	ENST00000411829.6	TSL:1	c.2603G>A	p.Arg868Gln	missense	Exon 15 of 15	ENSP00000416801.2	Q9HB75-2
	PIDD1	ENST00000525028.6	TSL:1	n.*2354G>A		non_coding_transcript_exon	Exon 15 of 15	ENSP00000436342.1	E9PPT6

Frequencies

GnomAD3 genomes AF: 0.000236 AC: 36 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00682

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000849 AC: 210 AN: 247414 AF XY: 0.00110

Gnomad AFR exome AF: 0.0000623

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000360

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000423 AC: 617 AN: 1459550 Hom.: 8 Cov.: 31 AF XY: 0.000606 AC XY: 440 AN XY: 726188

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000201 AC: 9 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00650 AC: 561 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51340

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111856

Other (OTH) AF: 0.000514 AC: 31 AN: 60360

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.000389 AC XY: 29 AN XY: 74492

African (AFR) AF: 0.00 AC: 0 AN: 41592

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00683 AC: 33 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000155 Hom.: 1

Bravo AF: 0.0000642

ExAC AF: 0.000981 AC: 119

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	6.6
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.079
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.16
Sift	Benign	0.23	T
Sift4G	Benign	0.25	T
Polyphen		0.23	B
Vest4		0.091
MutPred		0.19		Loss of solvent accessibility (P = 0.0442)
MVP		0.38
MPC		0.043
ClinPred		0.012	T
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.17
Mutation Taster		=92/8	polymorphism

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: rs373561275; hg19: chr11-799386; COSMIC: COSV100204120; COSMIC: COSV100204120;