chr11-799386-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

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. 15/21 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

Scores

1
18

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0790
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 Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PIDD1NM_145886.4 linkc.2654G>A p.Arg885Gln 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.2654G>A p.Arg885Gln missense_variant Exon 16 of 16 1 NM_145886.4 ENSP00000337797.5 Q9HB75-1
PANO1ENST00000678030.1 linkc.*1113C>T downstream_gene_variant ENSP00000503591.1 I0J062

Frequencies

GnomAD3 genomes
AF:
0.000236
AC:
36
AN:
152232
Hom.:
0
Cov.:
33
show subpopulations
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
GnomAD3 exomes
AF:
0.000849
AC:
210
AN:
247414
Hom.:
2
AF XY:
0.00110
AC XY:
148
AN XY:
134480
show subpopulations
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 SAS exome
AF:
0.00644
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
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00650
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.000514
GnomAD4 genome
AF:
0.000236
AC:
36
AN:
152350
Hom.:
0
Cov.:
33
AF XY:
0.000389
AC XY:
29
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000653
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00683
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000249
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

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Benign:1
Aug 08, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP
Pathogenic
0.32
D
MetaRNN
Benign
0.0045
T;T
MetaSVM
Benign
-0.50
T
MutationAssessor
Benign
0.90
.;L
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.90
N;N
REVEL
Benign
0.16
Sift
Benign
0.23
T;T
Sift4G
Benign
0.25
T;T
Polyphen
0.23
B;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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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