Genetic Variant FADD:p.Pro3Pro (chr11-70203468-G-T) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_003824.4(FADD):c.9G>T(p.Pro3Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000785 in 1,581,698 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P3P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00079 ( 7 hom. )

Consequence

FADD
NM_003824.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.31

Publications

1 publications found

Variant links:

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)

FADD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 11-70203468-G-T is Benign according to our data. Variant chr11-70203468-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 713705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.31 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

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.9G>T	p.Pro3Pro	synonymous	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.9G>T	p.Pro3Pro	synonymous	Exon 1 of 2	ENSP00000301838.5	Q13158
	FADD	ENST00000933048.1		c.9G>T	p.Pro3Pro	synonymous	Exon 1 of 2	ENSP00000603107.1

Frequencies

GnomAD3 genomes

AF:

0.000724

AC:

110

AN:

151910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00481

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000677

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00155

AC:

297

AN:

191334

AF XY:

0.00151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000689

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00678

Gnomad NFE exome

AF:

0.00158

Gnomad OTH exome

AF:

0.000993

GnomAD4 exome

AF:

0.000792

AC:

1132

AN:

1429672

Hom.:

Cov.:

AF XY:

0.000809

AC XY:

573

AN XY:

708616

show subpopulations

African (AFR)

AF:

0.0000917

AC:

AN:

32710

American (AMR)

AF:

0.0000250

AC:

AN:

39930

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25432

East Asian (EAS)

AF:

0.00

AC:

AN:

37816

South Asian (SAS)

AF:

0.00181

AC:

150

AN:

82958

European-Finnish (FIN)

AF:

0.00549

AC:

274

AN:

49922

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5634

European-Non Finnish (NFE)

AF:

0.000572

AC:

627

AN:

1096142

Other (OTH)

AF:

0.00130

AC:

AN:

59128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

133

200

266

333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000724

AC:

110

AN:

152026

Hom.:

Cov.:

AF XY:

0.000861

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41480

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00125

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00481

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000677

AC:

AN:

67936

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000597

Hom.:

Bravo

AF:

0.000332

Asia WGS

AF:

0.000289

AC:

AN:

3474

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

FADD-related immunodeficiency (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.5

(source)

DANN

Benign

0.92

PhyloP100

-1.3

PromoterAI

0.034

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over