Genetic Variant FAS:c.30+853C>T (chr10-88991759-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000043.6(FAS):c.30+853C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.573 in 151,954 control chromosomes in the GnomAD database, including 26,311 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.57 ( 26301 hom., cov: 31)

Exomes 𝑓: 0.64 ( 10 hom. )

Consequence

FAS
NM_000043.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.213

Publications

31 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 links:

ENSG00000286116 (HGNC:):

ENSG00000286116 links:

FAS-AS1 (HGNC:37128): (FAS antisense RNA 1)

FAS-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.77 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6 link	c.30+853C>T		intron_variant	Intron 1 of 8	ENST00000652046.1	NP_000034.1	P25445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1 link	c.30+853C>T		intron_variant	Intron 1 of 8		NM_000043.6	ENSP00000498466.1		P25445-1

Frequencies

GnomAD3 genomes

AF:

0.573

AC:

86978

AN:

151792

Hom.:

26244

Cov.:

show subpopulations

Gnomad AFR

AF:

0.777

Gnomad AMI

AF:

0.482

Gnomad AMR

AF:

0.551

Gnomad ASJ

AF:

0.432

Gnomad EAS

AF:

0.474

Gnomad SAS

AF:

0.445

Gnomad FIN

AF:

0.468

Gnomad MID

AF:

0.494

Gnomad NFE

AF:

0.496

Gnomad OTH

AF:

0.550

GnomAD4 exome

AF:

0.636

AC:

AN:

Hom.:

AF XY:

0.647

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.667

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.700

AC:

AN:

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.573

AC:

87101

AN:

151910

Hom.:

26301

Cov.:

AF XY:

0.570

AC XY:

42278

AN XY:

74232

show subpopulations

African (AFR)

AF:

0.777

AC:

32213

AN:

41440

American (AMR)

AF:

0.551

AC:

8419

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.432

AC:

1497

AN:

3466

East Asian (EAS)

AF:

0.474

AC:

2441

AN:

5150

South Asian (SAS)

AF:

0.444

AC:

2140

AN:

4816

European-Finnish (FIN)

AF:

0.468

AC:

4934

AN:

10534

Middle Eastern (MID)

AF:

0.500

AC:

147

AN:

294

European-Non Finnish (NFE)

AF:

0.496

AC:

33705

AN:

67926

Other (OTH)

AF:

0.553

AC:

1166

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1775

3551

5326

7102

8877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

712

1424

2136

2848

3560

<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:

0.550

Hom.:

7483

Bravo

AF:

0.589

Asia WGS

AF:

0.543

AC:

1887

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

6.1

(source)

DANN

Benign

0.78

PhyloP100

-0.21

PromoterAI

0.038

Neutral

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over