11-70203417-A-G

Variant names:

• chr11-70203417-A-G
• rs1131677
• NM_003824.4:c.-43A>G

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: -0.149
• Publications: 16 publications found

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]

FADD Gene-Disease associations (from GenCC):

• FADD-related immunodeficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003824.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FADD	NM_003824.4	MANE Select	c.-43A>G		5_prime_UTR	Exon 1 of 2	NP_003815.1	Q13158

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FADD	ENST00000301838.5	TSL:1 MANE Select	c.-43A>G		5_prime_UTR	Exon 1 of 2	ENSP00000301838.5	Q13158
	FADD	ENST00000933048.1		c.-43A>G		5_prime_UTR	Exon 1 of 2	ENSP00000603107.1

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

GnomAD2 exomes AF: 0.534 AC: 79246 AN: 148398 AF XY: 0.531

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 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

African (AFR) AF: 0.581 AC: 18293 AN: 31462

American (AMR) AF: 0.454 AC: 16249 AN: 35776

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 15607 AN: 25058

East Asian (EAS) AF: 0.632 AC: 22595 AN: 35770

South Asian (SAS) AF: 0.435 AC: 34485 AN: 79316

European-Finnish (FIN) AF: 0.560 AC: 26923 AN: 48088

Middle Eastern (MID) AF: 0.533 AC: 2410 AN: 4518

European-Non Finnish (NFE) AF: 0.575 AC: 620180 AN: 1078886

Other (OTH) AF: 0.570 AC: 32942 AN: 57798

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

African (AFR) AF: 0.588 AC: 24387 AN: 41480

American (AMR) AF: 0.481 AC: 7362 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 2201 AN: 3472

East Asian (EAS) AF: 0.648 AC: 3320 AN: 5120

South Asian (SAS) AF: 0.438 AC: 2108 AN: 4818

European-Finnish (FIN) AF: 0.561 AC: 5937 AN: 10576

Middle Eastern (MID) AF: 0.551 AC: 162 AN: 294

European-Non Finnish (NFE) AF: 0.573 AC: 38907 AN: 67888

Other (OTH) AF: 0.562 AC: 1186 AN: 2112

Alfa AF: 0.575 Hom.: 4629

Bravo AF: 0.561

Asia WGS AF: 0.548 AC: 1905 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.4
DANN	Benign	0.53
PhyloP100		-0.15
PromoterAI		-0.062	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1131677; hg19: chr11-70049523; COSMIC: COSV107384932; COSMIC: COSV107384932;