dbSNP rs28362318: FAS:p.Gln123Gln (chr10-89008923-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000043.6(FAS):c.369G>A(p.Gln123Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00737 in 1,613,954 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0076 ( 72 hom. )

Consequence

FAS
NM_000043.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.336

Publications

7 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 10-89008923-G-A is Benign according to our data. Variant chr10-89008923-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.336 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00523 (796/152318) while in subpopulation NFE AF = 0.00807 (549/68026). AF 95% confidence interval is 0.00751. There are 4 homozygotes in GnomAd4. There are 366 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

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	HGVSp	Effect	Exon Rank	Protein	UniProt
FAS	NM_000043.6	MANE Select	c.369G>A	p.Gln123Gln	synonymous	Exon 4 of 9	NP_000034.1	P25445-1
FAS	NM_001410956.1		c.414G>A	p.Gln138Gln	synonymous	Exon 4 of 9	NP_001397885.1	A0A8Q3SIR6
FAS	NM_152871.4		c.369G>A	p.Gln123Gln	synonymous	Exon 4 of 8	NP_690610.1	P25445-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FAS	ENST00000652046.1	MANE Select	c.369G>A	p.Gln123Gln	synonymous	Exon 4 of 9	ENSP00000498466.1	P25445-1
FAS	ENST00000357339.7	TSL:1	c.369G>A	p.Gln123Gln	synonymous	Exon 4 of 8	ENSP00000349896.2	P25445-6
FAS	ENST00000355279.2	TSL:1	c.369G>A	p.Gln123Gln	synonymous	Exon 4 of 8	ENSP00000347426.2	P25445-7

Frequencies

GnomAD3 genomes

AF:

0.00524

AC:

798

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00438

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00475

Gnomad FIN

AF:

0.00848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00807

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00620

AC:

1559

AN:

251454

AF XY:

0.00659

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00665

Gnomad ASJ exome

AF:

0.00188

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00688

Gnomad NFE exome

AF:

0.00757

Gnomad OTH exome

AF:

0.00863

GnomAD4 exome

AF:

0.00759

AC:

11092

AN:

1461636

Hom.:

Cov.:

AF XY:

0.00765

AC XY:

5565

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.000867

AC:

AN:

33464

American (AMR)

AF:

0.00664

AC:

297

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00195

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00761

AC:

656

AN:

86252

European-Finnish (FIN)

AF:

0.00674

AC:

360

AN:

53416

Middle Eastern (MID)

AF:

0.00399

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00836

AC:

9298

AN:

1111806

Other (OTH)

AF:

0.00626

AC:

378

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

607

1215

1822

2430

3037

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

356

712

1068

1424

1780

<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:

0.00523

AC:

796

AN:

152318

Hom.:

Cov.:

AF XY:

0.00491

AC XY:

366

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

41558

American (AMR)

AF:

0.00431

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00455

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00848

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00807

AC:

549

AN:

68026

Other (OTH)

AF:

0.00615

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

116

155

194

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00625

Hom.:

Bravo

AF:

0.00502

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00682

EpiControl

AF:

0.00812

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autoimmune lymphoproliferative syndrome type 1 (4)

not provided (3)

FAS-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

4.5

(source)

DANN

Benign

0.72

PhyloP100

0.34

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: -34

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