chr11-799435-C-A

Variant names:

• chr11-799435-C-A
• rs145288967
• NM_145886.4:c.2605G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_145886.4(PIDD1):​c.2605G>T​(p.Val869Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000608 in 1,611,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: PIDD1 NM_145886.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34
• Publications: 1 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]

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]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09182331).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000309 (47/152338) while in subpopulation AFR AF = 0.00113 (47/41586). AF 95% confidence interval is 0.000873. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2605G>T	p.Val869Leu	missense	Exon 16 of 16	NP_665893.2	Q9HB75-1
	PIDD1	NM_145887.4		c.2554G>T	p.Val852Leu	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.2605G>T	p.Val869Leu	missense	Exon 16 of 16	ENSP00000337797.5	Q9HB75-1
	PIDD1	ENST00000411829.6	TSL:1	c.2554G>T	p.Val852Leu	missense	Exon 15 of 15	ENSP00000416801.2	Q9HB75-2
	PIDD1	ENST00000525028.6	TSL:1	n.*2305G>T		non_coding_transcript_exon	Exon 15 of 15	ENSP00000436342.1	E9PPT6

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000101 AC: 25 AN: 246502 AF XY: 0.0000745

Gnomad AFR exome AF: 0.00118

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000350 AC: 51 AN: 1458786 Hom.: 0 Cov.: 31 AF XY: 0.0000331 AC XY: 24 AN XY: 725874

African (AFR) AF: 0.000777 AC: 26 AN: 33474

American (AMR) AF: 0.000224 AC: 10 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111876

Other (OTH) AF: 0.000166 AC: 10 AN: 60356

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74482

African (AFR) AF: 0.00113 AC: 47 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000200 Hom.: 0

Bravo AF: 0.000355

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000116 AC: 14

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual developmental disorder, autosomal recessive 75, with neuropsychiatric features and variant lissencephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.082
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Benign	0.092	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	1.6	L
PhyloP100		1.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.037	D
Polyphen		0.45	B
Vest4		0.37
MutPred		0.47		Loss of MoRF binding (P = 0.1077)
MVP		0.81
MPC		0.22
ClinPred		0.075	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.49
Mutation Taster		=85/15	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: rs145288967; hg19: chr11-799435;