11-799584-C-T

Variant names:

• chr11-799584-C-T
• rs150597726
• NM_145886.4:c.2475-19G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_145886.4(PIDD1):​c.2475-19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000543 in 1,579,030 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: PIDD1 NM_145886.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.165

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-799584-C-T is Benign according to our data. Variant chr11-799584-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2581676.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000683 (104/152320) while in subpopulation AMR AF= 0.0017 (26/15308). AF 95% confidence interval is 0.00119. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIDD1	NM_145886.4	c.2475-19G>A		intron_variant	Intron 15 of 15	ENST00000347755.10	NP_665893.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIDD1	ENST00000347755.10	c.2475-19G>A		intron_variant	Intron 15 of 15	1	NM_145886.4	ENSP00000337797.5

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000563 AC: 121 AN: 214768 Hom.: 0 AF XY: 0.000500 AC XY: 59 AN XY: 117926

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.000124

Gnomad EAS exome AF: 0.000225

Gnomad SAS exome AF: 0.000223

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000633

Gnomad OTH exome AF: 0.000740

GnomAD4 exome AF: 0.000528 AC: 754 AN: 1426710 Hom.: 1 Cov.: 31 AF XY: 0.000539 AC XY: 381 AN XY: 707082

Gnomad4 AFR exome AF: 0.00175

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.0000405

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.000156

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000522

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.000683 AC: 104 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000645 AC XY: 48 AN XY: 74472

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000342 Hom.: 0

Bravo AF: 0.000654

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 11, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LRDD c.2475-19G>A alters a non-conserved nucleotide located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00053 in 246098 control chromosomes. To our knowledge, no occurrence of c.2475-19G>A in individuals affected with Intellectual Developmental Disorder, Autosomal Recessive 75, With Neuropsychiatric Features And Variant Lissencephaly and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Other links and lift over

dbSNP: rs150597726; hg19: chr11-799584; COSMIC: COSV100204313; COSMIC: COSV100204313;