10-89012072-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000043.6(FAS):c.642T>C(p.Thr214Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 1,611,060 control chromosomes in the GnomAD database, including 428,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T214T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.73 ( 40584 hom., cov: 33)

Exomes 𝑓: 0.73 ( 388317 hom. )

Consequence

FAS
NM_000043.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: -0.710

Publications

88 publications found

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 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

FAS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 10-89012072-T-C is Benign according to our data. Variant chr10-89012072-T-C is described in ClinVar as Benign. ClinVar VariationId is 254734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6 link	c.642T>C	p.Thr214Thr	synonymous_variant	Exon 7 of 9	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1 link	c.642T>C	p.Thr214Thr	synonymous_variant	Exon 7 of 9		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes

AF:

0.727

AC:

110589

AN:

152056

Hom.:

40556

Cov.:

show subpopulations

Gnomad AFR

AF:

0.681

Gnomad AMI

AF:

0.636

Gnomad AMR

AF:

0.798

Gnomad ASJ

AF:

0.748

Gnomad EAS

AF:

0.973

Gnomad SAS

AF:

0.819

Gnomad FIN

AF:

0.794

Gnomad MID

AF:

0.731

Gnomad NFE

AF:

0.704

Gnomad OTH

AF:

0.746

GnomAD2 exomes

AF:

0.766

AC:

192259

AN:

251130

AF XY:

0.763

show subpopulations

Gnomad AFR exome

AF:

0.676

Gnomad AMR exome

AF:

0.857

Gnomad ASJ exome

AF:

0.733

Gnomad EAS exome

AF:

0.983

Gnomad FIN exome

AF:

0.789

Gnomad NFE exome

AF:

0.699

Gnomad OTH exome

AF:

0.748

GnomAD4 exome

AF:

0.727

AC:

1060736

AN:

1458886

Hom.:

388317

Cov.:

AF XY:

0.729

AC XY:

529531

AN XY:

725916

show subpopulations

African (AFR)

AF:

0.677

AC:

22619

AN:

33406

American (AMR)

AF:

0.847

AC:

37865

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.737

AC:

19244

AN:

26098

East Asian (EAS)

AF:

0.962

AC:

38167

AN:

39668

South Asian (SAS)

AF:

0.820

AC:

70685

AN:

86198

European-Finnish (FIN)

AF:

0.787

AC:

41981

AN:

53372

Middle Eastern (MID)

AF:

0.730

AC:

4202

AN:

5756

European-Non Finnish (NFE)

AF:

0.704

AC:

781409

AN:

1109402

Other (OTH)

AF:

0.739

AC:

44564

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

13133

26267

39400

52534

65667

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19808

39616

59424

79232

99040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.727

AC:

110674

AN:

152174

Hom.:

40584

Cov.:

AF XY:

0.735

AC XY:

54652

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.681

AC:

28262

AN:

41506

American (AMR)

AF:

0.799

AC:

12220

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.748

AC:

2593

AN:

3468

East Asian (EAS)

AF:

0.974

AC:

5051

AN:

5188

South Asian (SAS)

AF:

0.819

AC:

3951

AN:

4826

European-Finnish (FIN)

AF:

0.794

AC:

8404

AN:

10582

Middle Eastern (MID)

AF:

0.731

AC:

215

AN:

294

European-Non Finnish (NFE)

AF:

0.704

AC:

47833

AN:

67990

Other (OTH)

AF:

0.742

AC:

1565

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1576

3152

4727

6303

7879

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

842

1684

2526

3368

4210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.713

Hom.:

194384

Bravo

AF:

0.724

Asia WGS

AF:

0.864

AC:

3005

AN:

3478

EpiCase

AF:

0.695

EpiControl

AF:

0.699

ClinVar

Significance: Benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

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 93% of patients studied by a panel of primary immunodeficiencies. Number of patients: 89. Only high quality variants are reported. -

Autoimmune lymphoproliferative syndrome type 1

Benign:3

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. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2Other:1

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: 15350189) -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

1.1

(source)

DANN

Benign

0.50

PhyloP100

-0.71

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over