10-89015015-A-T

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.*565A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0755 in 532,728 control chromosomes in the GnomAD database, including 2,086 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 521 hom., cov: 32)

Exomes 𝑓: 0.078 ( 1565 hom. )

Consequence

FAS
NM_000043.6 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.18

Publications

22 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
Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
autoimmune lymphoproliferative syndrome type 1
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

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=-0.86).

BP6

Variant 10-89015015-A-T is Benign according to our data. Variant chr10-89015015-A-T is described in ClinVar as Benign. ClinVar VariationId is 301537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 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
FAS	NM_000043.6	MANE Select	c.*565A>T	3_prime_UTR	Exon 9 of 9	NP_000034.1
FAS	NM_001410956.1		c.*565A>T	3_prime_UTR	Exon 9 of 9	NP_001397885.1
FAS	NM_152871.4		c.*565A>T	3_prime_UTR	Exon 8 of 8	NP_690610.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
FAS	ENST00000652046.1	MANE Select	c.*565A>T	3_prime_UTR	Exon 9 of 9	ENSP00000498466.1
FAS	ENST00000357339.7	TSL:1	c.*565A>T	3_prime_UTR	Exon 8 of 8	ENSP00000349896.2
FAS	ENST00000355740.8	TSL:1	c.*896A>T	3_prime_UTR	Exon 8 of 8	ENSP00000347979.3

Frequencies

GnomAD3 genomes

AF:

0.0684

AC:

10405

AN:

152184

Hom.:

521

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0192

Gnomad AMI

AF:

0.0548

Gnomad AMR

AF:

0.0582

Gnomad ASJ

AF:

0.0876

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0167

Gnomad FIN

AF:

0.0518

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.0646

GnomAD2 exomes

AF:

0.0659

AC:

8570

AN:

130106

AF XY:

0.0647

show subpopulations

Gnomad AFR exome

AF:

0.0150

Gnomad AMR exome

AF:

0.0492

Gnomad ASJ exome

AF:

0.0954

Gnomad EAS exome

AF:

0.000384

Gnomad FIN exome

AF:

0.0569

Gnomad NFE exome

AF:

0.112

Gnomad OTH exome

AF:

0.0710

GnomAD4 exome

AF:

0.0784

AC:

29832

AN:

380426

Hom.:

1565

Cov.:

AF XY:

0.0733

AC XY:

15233

AN XY:

207830

show subpopulations

African (AFR)

AF:

0.0174

AC:

214

AN:

12312

American (AMR)

AF:

0.0493

AC:

1461

AN:

29628

Ashkenazi Jewish (ASJ)

AF:

0.0941

AC:

1493

AN:

15868

East Asian (EAS)

AF:

0.0000977

AC:

AN:

20468

South Asian (SAS)

AF:

0.0171

AC:

1028

AN:

60186

European-Finnish (FIN)

AF:

0.0651

AC:

808

AN:

12406

Middle Eastern (MID)

AF:

0.0496

AC:

AN:

1632

European-Non Finnish (NFE)

AF:

0.111

AC:

23021

AN:

207248

Other (OTH)

AF:

0.0834

AC:

1724

AN:

20678

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1728

3456

5183

6911

8639

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.0683

AC:

10403

AN:

152302

Hom.:

521

Cov.:

AF XY:

0.0647

AC XY:

4819

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0191

AC:

796

AN:

41582

American (AMR)

AF:

0.0580

AC:

887

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0876

AC:

304

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.0166

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0518

AC:

550

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.112

AC:

7595

AN:

68000

Other (OTH)

AF:

0.0639

AC:

135

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

490

980

1471

1961

2451

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

228

342

456

570

<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:

0.0876

Hom.:

129

Bravo

AF:

0.0678

Asia WGS

AF:

0.0100

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

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

-0.86

CADD

Benign

4.7

(source)

DANN

Benign

0.48

PhyloP100

1.2

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