11-70203417-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003824.4(FADD):c.-43A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.565 in 1,548,628 control chromosomes in the GnomAD database, including 249,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (24505 hom., cov: 32)
  • Exomes 𝑓: 0.57 (224738 hom.)
• Consequence: FADD NM_003824.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.149

Genes affected

FADD (HGNC:3573): (Fas associated via death domain) The protein encoded by this gene is an adaptor molecule that interacts with various cell surface receptors and mediates cell apoptotic signals. Through its C-terminal death domain, this protein can be recruited by TNFRSF6/Fas-receptor, tumor necrosis factor receptor, TNFRSF25, and TNFSF10/TRAIL-receptor, and thus it participates in the death signaling initiated by these receptors. Interaction of this protein with the receptors unmasks the N-terminal effector domain of this protein, which allows it to recruit caspase-8, and thereby activate the cysteine protease cascade. Knockout studies in mice also suggest the importance of this protein in early T cell development. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 11-70203417-A-G is Benign according to our data. Variant chr11-70203417-A-G is described in ClinVar as [Benign]. Clinvar id is 1174392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FADD	NM_003824.4	c.-43A>G		5_prime_UTR_variant	1/2	ENST00000301838.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FADD	ENST00000301838.5	c.-43A>G		5_prime_UTR_variant	1/2	1	NM_003824.4	P1

Frequencies

GnomAD3 genomes AF: 0.565 AC: 85824 AN: 151840 Hom.: 24473 Cov.: 32

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.634

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.438

Gnomad FIN AF: 0.561

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.573

Gnomad OTH AF: 0.561

GnomAD3 exomes AF: 0.534 AC: 79246 AN: 148398 Hom.: 21703 AF XY: 0.531 AC XY: 42644 AN XY: 80332

Gnomad AFR exome AF: 0.584

Gnomad AMR exome AF: 0.450

Gnomad ASJ exome AF: 0.614

Gnomad EAS exome AF: 0.616

Gnomad SAS exome AF: 0.433

Gnomad FIN exome AF: 0.562

Gnomad NFE exome AF: 0.570

Gnomad OTH exome AF: 0.561

GnomAD4 exome AF: 0.565 AC: 789684 AN: 1396672 Hom.: 224738 Cov.: 50 AF XY: 0.562 AC XY: 387003 AN XY: 689120

Gnomad4 AFR exome AF: 0.581

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.623

Gnomad4 EAS exome AF: 0.632

Gnomad4 SAS exome AF: 0.435

Gnomad4 FIN exome AF: 0.560

Gnomad4 NFE exome AF: 0.575

Gnomad4 OTH exome AF: 0.570

GnomAD4 genome AF: 0.565 AC: 85907 AN: 151956 Hom.: 24505 Cov.: 32 AF XY: 0.562 AC XY: 41745 AN XY: 74248

Gnomad4 AFR AF: 0.588

Gnomad4 AMR AF: 0.481

Gnomad4 ASJ AF: 0.634

Gnomad4 EAS AF: 0.648

Gnomad4 SAS AF: 0.438

Gnomad4 FIN AF: 0.561

Gnomad4 NFE AF: 0.573

Gnomad4 OTH AF: 0.562

Alfa AF: 0.575 Hom.: 4629

Bravo AF: 0.561

Asia WGS AF: 0.548 AC: 1905 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	6.4
Dann	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1131677; hg19: chr11-70049523;