rs2229521

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000043.6(FAS):c.222A>G(p.Thr74Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.049 in 1,613,964 control chromosomes in the GnomAD database, including 2,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.040 ( 213 hom., cov: 32)

Exomes 𝑓: 0.050 ( 2597 hom. )

Consequence

FAS
NM_000043.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.472

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 10-89007725-A-G is Benign according to our data. Variant chr10-89007725-A-G is described in ClinVar as [Benign]. Clinvar id is 301527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-89007725-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.472 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6 link	c.222A>G	p.Thr74Thr	synonymous_variant	Exon 3 of 9	ENST00000652046.1	NP_000034.1	P25445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1 link	c.222A>G	p.Thr74Thr	synonymous_variant	Exon 3 of 9		NM_000043.6	ENSP00000498466.1		P25445-1

Frequencies

GnomAD3 genomes

AF:

0.0404

AC:

6148

AN:

152152

Hom.:

205

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0103

Gnomad AMI

AF:

0.0165

Gnomad AMR

AF:

0.115

Gnomad ASJ

AF:

0.0225

Gnomad EAS

AF:

0.0194

Gnomad SAS

AF:

0.0558

Gnomad FIN

AF:

0.0380

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0441

Gnomad OTH

AF:

0.0445

GnomAD3 exomes

AF:

0.0633

AC:

15917

AN:

251316

Hom.:

1111

AF XY:

0.0582

AC XY:

7903

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.0107

Gnomad AMR exome

AF:

0.213

Gnomad ASJ exome

AF:

0.0242

Gnomad EAS exome

AF:

0.0154

Gnomad SAS exome

AF:

0.0614

Gnomad FIN exome

AF:

0.0372

Gnomad NFE exome

AF:

0.0426

Gnomad OTH exome

AF:

0.0559

GnomAD4 exome

AF:

0.0499

AC:

72982

AN:

1461692

Hom.:

2597

Cov.:

AF XY:

0.0496

AC XY:

36051

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.00894

Gnomad4 AMR exome

AF:

0.199

Gnomad4 ASJ exome

AF:

0.0231

Gnomad4 EAS exome

AF:

0.0240

Gnomad4 SAS exome

AF:

0.0617

Gnomad4 FIN exome

AF:

0.0364

Gnomad4 NFE exome

AF:

0.0468

Gnomad4 OTH exome

AF:

0.0444

GnomAD4 genome

AF:

0.0405

AC:

6166

AN:

152272

Hom.:

213

Cov.:

AF XY:

0.0419

AC XY:

3119

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0103

Gnomad4 AMR

AF:

0.116

Gnomad4 ASJ

AF:

0.0225

Gnomad4 EAS

AF:

0.0193

Gnomad4 SAS

AF:

0.0558

Gnomad4 FIN

AF:

0.0380

Gnomad4 NFE

AF:

0.0441

Gnomad4 OTH

AF:

0.0440

Alfa

AF:

0.0422

Hom.:

141

Bravo

AF:

0.0481

Asia WGS

AF:

0.0390

AC:

135

AN:

3478

EpiCase

AF:

0.0435

EpiControl

AF:

0.0416

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10402071) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autoimmune lymphoproliferative syndrome type 1

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 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. -

not specified

Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 21% of patients studied by a panel of primary immunodeficiencies. Number of patients: 20. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.6

DANN

Benign

0.35

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

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