rs377337130

Variant names:

• chr10-89014309-A-C
• rs377337130
• NM_000043.6:c.867A>C

Your query was ambiguous. Multiple possible variants found:

• chr10-89014309-A-C
• chr10-89014309-A-G
• chr10-89014309-A-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_000043.6(FAS):​c.867A>C​(p.Glu289Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,613,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E289G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: FAS NM_000043.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.60
• Publications: 3 publications found

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

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• autoimmune lymphoproliferative syndrome type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a domain Death (size 84) in uniprot entity TNR6_HUMAN there are 27 pathogenic changes around while only 2 benign (93%) in NM_000043.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.014647186).
• BP6: Variant 10-89014309-A-C is Benign according to our data. Variant chr10-89014309-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 301531.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6	c.867A>C	p.Glu289Asp	missense_variant	Exon 9 of 9	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.867A>C	p.Glu289Asp	missense_variant	Exon 9 of 9		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000517 AC: 13 AN: 251282 AF XY: 0.0000810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000985 AC: 144 AN: 1461678 Hom.: 0 Cov.: 31 AF XY: 0.000102 AC XY: 74 AN XY: 727134

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000122 AC: 136 AN: 1111924

Other (OTH) AF: 0.000116 AC: 7 AN: 60390

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5208

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 1 Uncertain:1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 289 of the FAS protein (p.Glu289Asp). This variant is present in population databases (rs377337130, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 301531). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FAS protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Benign:1

Aug 14, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.040
DANN	Benign	0.098
DEOGEN2	Uncertain	0.42	T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.28	T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-2.1	N;.
PhyloP100		-1.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.2	N;N
REVEL	Benign	0.15
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.052
MutPred		0.49		Loss of ubiquitination at K287 (P = 0.1191);.;
MVP		0.41
MPC		0.20
ClinPred		0.020	T
GERP RS		-5.9
Varity_R		0.24
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs377337130; hg19: chr10-90774066;