rs56006128

Positions:

chr10-89012010-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000043.6(FAS):c.580G>A(p.Glu194Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,886 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0018 ( 4 hom. )

Consequence

FAS
NM_000043.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:8O:1

Conservation

PhyloP100: -1.15

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 144) in uniprot entity TNR6_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_000043.6

BP4

Computational evidence support a benign effect (MetaRNN=0.0061986744).

BP6

Variant 10-89012010-G-A is Benign according to our data. Variant chr10-89012010-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134374.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, not_provided=1, Uncertain_significance=6}. Variant chr10-89012010-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00142 (216/152306) while in subpopulation NFE AF= 0.00232 (158/68030). AF 95% confidence interval is 0.00203. There are 0 homozygotes in gnomad4. There are 103 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAS	NM_000043.6 linkuse as main transcript	c.580G>A	p.Glu194Lys	missense_variant	7/9	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1 linkuse as main transcript	c.580G>A	p.Glu194Lys	missense_variant	7/9		NM_000043.6	ENSP00000498466	A2	P25445-1

Frequencies

GnomAD3 genomes

AF:

0.00142

AC:

216

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00232

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00154

AC:

388

AN:

251260

Hom.:

AF XY:

0.00182

AC XY:

247

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000753

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00167

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00247

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00177

AC:

2589

AN:

1461580

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

1350

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00116

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00194

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.00193

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00142

AC:

216

AN:

152306

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

103

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00232

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00211

Hom.:

Bravo

AF:

0.00142

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00337

AC:

ExAC

AF:

0.00180

AC:

219

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00360

EpiControl

AF:

0.00403

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 1

Uncertain:3Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	FAS NM_000043.5 exon7 p.Glu194Lys (c.580G>A): This variant has been reported in the literature in at least one individual with autoimmune lymphoproliferative syndrome (ALPS)(Campagnoli 2006 PMID:16537120, Boggio 2013 PMID:24043286). This variant is present in 0.2% (306/126586) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/dbsnp/rs56006128). This variant is present in ClinVar (Variation ID:134374). Evolutionary conservation and computational predictive tools for this variant are unclear. In vitro functional studies suggest that this variant will impact the protein (Boggio 2013 PMID:24043286). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 06, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	FAS: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2018	The E194K variant in the FAS gene has been reported previously in association with autoimmune lymphoproliferative syndrome type 1A (Campagnoli et al., 2006; Rao et al., 2009). The E194K variant is observed in 306/126,586 (0.24%) alleles from individuals of non-Finnish European background and 414/277,020 (0.15%) total alleles, including one homozygous individual, in large population cohorts (Lek et al., 2016). The E194K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Functional studies have shown that E194K decreases the function of the FAS protein (Boggio et al., 2013). We interpret E194K as a variant of uncertain significance. -

not specified

Uncertain:1Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 23, 2024	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 14, 2017	- -

FAS-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2020

This variant is classified as likely 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

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.090

CADD

Benign

0.92

DANN

Benign

0.15

DEOGEN2

Benign

0.31

T;.;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0034

LIST_S2

Benign

0.52

T;T;T;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.0062

T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

-0.34

N;.;.;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.49

N;N;N;N

REVEL

Uncertain

0.45

Sift

Benign

0.72

T;T;T;T

Sift4G

Benign

0.62

T;T;T;T

Polyphen

0.011

B;.;B;.

Vest4

0.069

MVP

0.98

MPC

0.24

ClinPred

0.00088

Varity_R

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over