rs9658776

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000043.6(FAS):c.*765T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0521 in 534,864 control chromosomes in the GnomAD database, including 1,316 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 213 hom., cov: 32)

Exomes 𝑓: 0.057 ( 1103 hom. )

Consequence

FAS
NM_000043.6 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.307

Publications

5 publications found

Variant links:

Genes affected

FAS (HGNC:11920): (Fas cell surface death receptor) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains a death domain. It has been shown to play a central role in the physiological regulation of programmed cell death, and has been implicated in the pathogenesis of various malignancies and diseases of the immune system. The interaction of this receptor with its ligand allows the formation of a death-inducing signaling complex that includes Fas-associated death domain protein (FADD), caspase 8, and caspase 10. The autoproteolytic processing of the caspases in the complex triggers a downstream caspase cascade, and leads to apoptosis. This receptor has been also shown to activate NF-kappaB, MAPK3/ERK1, and MAPK8/JNK, and is found to be involved in transducing the proliferating signals in normal diploid fibroblast and T cells. Several alternatively spliced transcript variants have been described, some of which are candidates for nonsense-mediated mRNA decay (NMD). The isoforms lacking the transmembrane domain may negatively regulate the apoptosis mediated by the full length isoform. [provided by RefSeq, Mar 2011]

FAS Gene-Disease associations (from GenCC):

autoimmune lymphoproliferative syndrome type 1
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
autoimmune lymphoproliferative syndrome
Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet

FAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 10-89015215-T-C is Benign according to our data. Variant chr10-89015215-T-C is described in ClinVar as Benign. ClinVar VariationId is 301541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000043.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FAS	NM_000043.6	MANE Select	c.*765T>C	3_prime_UTR	Exon 9 of 9	NP_000034.1	P25445-1
FAS	NM_001410956.1		c.*765T>C	3_prime_UTR	Exon 9 of 9	NP_001397885.1	A0A8Q3SIR6
FAS	NM_152871.4		c.*765T>C	3_prime_UTR	Exon 8 of 8	NP_690610.1	P25445-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FAS	ENST00000652046.1	MANE Select	c.*765T>C	3_prime_UTR	Exon 9 of 9	ENSP00000498466.1	P25445-1
FAS	ENST00000357339.7	TSL:1	c.*765T>C	3_prime_UTR	Exon 8 of 8	ENSP00000349896.2	P25445-6
FAS	ENST00000355740.8	TSL:1	c.*1096T>C	3_prime_UTR	Exon 8 of 8	ENSP00000347979.3	K9J972

Frequencies

GnomAD3 genomes

AF:

0.0404

AC:

6143

AN:

152148

Hom.:

205

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0103

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.0194

Gnomad SAS

AF:

0.0556

Gnomad FIN

AF:

0.0379

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0442

Gnomad OTH

AF:

0.0445

GnomAD2 exomes

AF:

0.0724

AC:

9440

AN:

130450

AF XY:

0.0660

show subpopulations

Gnomad AFR exome

AF:

0.0113

Gnomad AMR exome

AF:

0.206

Gnomad ASJ exome

AF:

0.0249

Gnomad EAS exome

AF:

0.0145

Gnomad FIN exome

AF:

0.0407

Gnomad NFE exome

AF:

0.0434

Gnomad OTH exome

AF:

0.0577

GnomAD4 exome

AF:

0.0567

AC:

21696

AN:

382598

Hom.:

1103

Cov.:

AF XY:

0.0554

AC XY:

11583

AN XY:

209126

show subpopulations

African (AFR)

AF:

0.0119

AC:

148

AN:

12442

American (AMR)

AF:

0.201

AC:

5971

AN:

29770

Ashkenazi Jewish (ASJ)

AF:

0.0241

AC:

384

AN:

15906

East Asian (EAS)

AF:

0.0225

AC:

462

AN:

20566

South Asian (SAS)

AF:

0.0627

AC:

3783

AN:

60348

European-Finnish (FIN)

AF:

0.0391

AC:

486

AN:

12422

Middle Eastern (MID)

AF:

0.0439

AC:

AN:

1640

European-Non Finnish (NFE)

AF:

0.0453

AC:

9464

AN:

208704

Other (OTH)

AF:

0.0445

AC:

926

AN:

20800

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1356

2712

4069

5425

6781

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.0405

AC:

6161

AN:

152266

Hom.:

213

Cov.:

AF XY:

0.0418

AC XY:

3112

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0102

AC:

425

AN:

41566

American (AMR)

AF:

0.116

AC:

1770

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3472

East Asian (EAS)

AF:

0.0193

AC:

100

AN:

5188

South Asian (SAS)

AF:

0.0556

AC:

268

AN:

4818

European-Finnish (FIN)

AF:

0.0379

AC:

402

AN:

10606

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0442

AC:

3004

AN:

68006

Other (OTH)

AF:

0.0440

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

292

585

877

1170

1462

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0450

Hom.:

239

Bravo

AF:

0.0481

Asia WGS

AF:

0.0390

AC:

135

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autoimmune lymphoproliferative syndrome type 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

4.4

(source)

DANN

Benign

0.69

PhyloP100

0.31

Mutation Taster

=100/0

polymorphism (auto)

(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