rs56006128

chr10-89012010-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:7 O:1
• Conservation: PhyloP100: -1.15

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 144) in uniprot entity TNR6_HUMAN there are 39 pathogenic changes around while only 8 benign (83%) 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, Uncertain_significance=5, not_provided=1}. 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. This position pass quality control queck.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.580G>A	p.Glu194Lys	missense_variant	7/9		NM_000043.6	A2

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152188 Hom.: 0 Cov.: 33

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.: 1 AF XY: 0.00182 AC XY: 247 AN XY: 135814

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.: 4 Cov.: 30 AF XY: 0.00186 AC XY: 1350 AN XY: 727110

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.: 0 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74474

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.: 0

Bravo AF: 0.00142

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00180 AC: 219

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00403

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:7 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 1 Uncertain:3 Benign:2

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]. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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	- -

not provided Uncertain:1 Benign:4

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. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus 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	Jan 01, 2024	FAS: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Uncertain:1 Other:1

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, criteria provided, single submitter

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	T
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	N
LIST_S2	Benign	0.52	T;T;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0062	T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	-0.34	N;.;.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
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	T
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

Other links and lift over

dbSNP: rs56006128; hg19: chr10-90771767; COSMIC: COSV100570917; COSMIC: COSV100570917;