Genetic Variant NM_000043.6:c.222A>G (chr10-89007725-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

18 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 -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 VariationId is 301527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000043.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FAS	NM_000043.6	MANE Select	c.222A>G	p.Thr74Thr	synonymous	Exon 3 of 9	NP_000034.1
FAS	NM_001410956.1		c.267A>G	p.Thr89Thr	synonymous	Exon 3 of 9	NP_001397885.1
FAS	NM_152871.4		c.222A>G	p.Thr74Thr	synonymous	Exon 3 of 8	NP_690610.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FAS	ENST00000652046.1	MANE Select	c.222A>G	p.Thr74Thr	synonymous	Exon 3 of 9	ENSP00000498466.1
FAS	ENST00000357339.7	TSL:1	c.222A>G	p.Thr74Thr	synonymous	Exon 3 of 8	ENSP00000349896.2
FAS	ENST00000355279.2	TSL:1	c.222A>G	p.Thr74Thr	synonymous	Exon 3 of 8	ENSP00000347426.2

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

GnomAD2 exomes

AF:

0.0633

AC:

15917

AN:

251316

AF XY:

0.0582

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 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

African (AFR)

AF:

0.00894

AC:

299

AN:

33462

American (AMR)

AF:

0.199

AC:

8897

AN:

44662

Ashkenazi Jewish (ASJ)

AF:

0.0231

AC:

603

AN:

26128

East Asian (EAS)

AF:

0.0240

AC:

953

AN:

39700

South Asian (SAS)

AF:

0.0617

AC:

5323

AN:

86258

European-Finnish (FIN)

AF:

0.0364

AC:

1942

AN:

53410

Middle Eastern (MID)

AF:

0.0418

AC:

241

AN:

5768

European-Non Finnish (NFE)

AF:

0.0468

AC:

52044

AN:

1111912

Other (OTH)

AF:

0.0444

AC:

2680

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

4525

9050

13576

18101

22626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2026

4052

6078

8104

10130

<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:

0.0405

AC:

6166

AN:

152272

Hom.:

213

Cov.:

AF XY:

0.0419

AC XY:

3119

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0103

AC:

428

AN:

41558

American (AMR)

AF:

0.116

AC:

1771

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

AN:

3472

East Asian (EAS)

AF:

0.0193

AC:

100

AN:

5182

South Asian (SAS)

AF:

0.0558

AC:

269

AN:

4820

European-Finnish (FIN)

AF:

0.0380

AC:

404

AN:

10624

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0441

AC:

3002

AN:

68018

Other (OTH)

AF:

0.0440

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

302

605

907

1210

1512

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0437

Hom.:

222

Bravo

AF:

0.0481

Asia WGS

AF:

0.0390

AC:

135

AN:

3478

EpiCase

AF:

0.0435

EpiControl

AF:

0.0416

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autoimmune lymphoproliferative syndrome type 1 (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

1.6

(source)

DANN

Benign

0.35

PhyloP100

0.47

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over