11-799318-C-T

Variant names:

• chr11-799318-C-T
• NM_145886.4:c.2722G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_145886.4(PIDD1):​c.2722G>A​(p.Ala908Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PIDD1 NM_145886.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00800

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054884642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIDD1	NM_145886.4	c.2722G>A	p.Ala908Thr	missense_variant	Exon 16 of 16	ENST00000347755.10	NP_665893.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIDD1	ENST00000347755.10	c.2722G>A	p.Ala908Thr	missense_variant	Exon 16 of 16	1	NM_145886.4	ENSP00000337797.5
PANO1	ENST00000678030.1	c.*1045C>T		downstream_gene_variant				ENSP00000503591.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1447366 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 719070

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2722G>A (p.A908T) alteration is located in exon 16 (coding exon 15) of the PIDD1 gene. This alteration results from a G to A substitution at nucleotide position 2722, causing the alanine (A) at amino acid position 908 to be replaced by a threonine (T). 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	Benign	0.073
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	.;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.055	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	.;L
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.055
Sift	Benign	0.076	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.15		.;Gain of glycosylation at A908 (P = 0.0017);
MVP		0.19
MPC		0.038
ClinPred		0.14	T
GERP RS		-0.48
Varity_R		0.094
gMVP		0.38

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-799318;