11-799403-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_145886.4(PIDD1):​c.2637G>C​(p.Lys879Asn) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K879R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

PIDD1
NM_145886.4 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.82
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PIDD1NM_145886.4 linkc.2637G>C p.Lys879Asn missense_variant Exon 16 of 16 ENST00000347755.10 NP_665893.2 Q9HB75-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PIDD1ENST00000347755.10 linkc.2637G>C p.Lys879Asn missense_variant Exon 16 of 16 1 NM_145886.4 ENSP00000337797.5 Q9HB75-1
PANO1ENST00000678030.1 linkc.*1130C>G downstream_gene_variant ENSP00000503591.1 I0J062

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Jan 03, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2637G>C (p.K879N) alteration is located in exon 16 (coding exon 15) of the PIDD1 gene. This alteration results from a G to C substitution at nucleotide position 2637, causing the lysine (K) at amino acid position 879 to be replaced by an asparagine (N). 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
Pathogenic
0.86
BayesDel_addAF
Uncertain
0.062
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.41
.;T
Eigen
Uncertain
0.27
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Benign
0.69
D
LIST_S2
Uncertain
0.87
D;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.83
D;D
MetaSVM
Uncertain
0.52
D
MutationAssessor
Uncertain
2.4
.;M
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-1.9
N;N
REVEL
Uncertain
0.35
Sift
Pathogenic
0.0
D;T
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.61
MutPred
0.18
.;Loss of methylation at K879 (P = 0.0141);
MVP
0.88
MPC
0.30
ClinPred
0.96
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.20
gMVP
0.48

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: chr11-799403; API