rs28362318

Variant summary

Our verdict is Benign. Variant got -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

2

Clinical Significance

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

Conservation

PhyloP100: 0.336
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 210992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-89008923-G-A is described in Lovd as [Likely_benign].
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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FASNM_000043.6 linkc.369G>A p.Gln123Gln synonymous_variant Exon 4 of 9 ENST00000652046.1 NP_000034.1 P25445-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FASENST00000652046.1 linkc.369G>A p.Gln123Gln synonymous_variant Exon 4 of 9 NM_000043.6 ENSP00000498466.1 P25445-1

Frequencies

GnomAD3 genomes
AF:
0.00524
AC:
798
AN:
152200
Hom.:
4
Cov.:
33
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
GnomAD3 exomes
AF:
0.00620
AC:
1559
AN:
251454
Hom.:
18
AF XY:
0.00659
AC XY:
895
AN XY:
135900
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 SAS exome
AF:
0.00748
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.:
72
Cov.:
31
AF XY:
0.00765
AC XY:
5565
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.000867
Gnomad4 AMR exome
AF:
0.00664
Gnomad4 ASJ exome
AF:
0.00195
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00761
Gnomad4 FIN exome
AF:
0.00674
Gnomad4 NFE exome
AF:
0.00836
Gnomad4 OTH exome
AF:
0.00626
GnomAD4 genome
AF:
0.00523
AC:
796
AN:
152318
Hom.:
4
Cov.:
33
AF XY:
0.00491
AC XY:
366
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00128
Gnomad4 AMR
AF:
0.00431
Gnomad4 ASJ
AF:
0.000865
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00455
Gnomad4 FIN
AF:
0.00848
Gnomad4 NFE
AF:
0.00807
Gnomad4 OTH
AF:
0.00615
Alfa
AF:
0.00625
Hom.:
3
Bravo
AF:
0.00502
Asia WGS
AF:
0.00144
AC:
5
AN:
3478
EpiCase
AF:
0.00682
EpiControl
AF:
0.00812

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 1 Benign:4
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 13, 2017
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 28, 2017
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:3
Sep 16, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

FAS: BP4, BP7, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

not specified Benign:1
Aug 23, 2018
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

FAS-related disorder Benign:1
Jul 26, 2019
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.43
CADD
Benign
4.5
DANN
Benign
0.72

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs28362318; hg19: chr10-90768680; COSMIC: COSV100570909; COSMIC: COSV100570909; API