rs2229521

Variant names:

• chr10-89007725-A-G
• rs2229521
• NM_000043.6:c.222A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001410956.1(FAS):​c.267A>G​(p.Thr89Thr) 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_001410956.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.472
• Publications: 18 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: 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_001410956.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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.: 32

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

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.: 35 AF XY: 0.0496 AC XY: 36051 AN XY: 727152

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

GnomAD4 genome AF: 0.0405 AC: 6166 AN: 152272 Hom.: 213 Cov.: 32 AF XY: 0.0419 AC XY: 3119 AN XY: 74450

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: 78 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: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0441 AC: 3002 AN: 68018

Other (OTH) AF: 0.0440 AC: 93 AN: 2112

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

Pathogenic	VUS	Benign	Condition
-	-	2	Autoimmune lymphoproliferative syndrome type 1 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.6
DANN	Benign	0.35
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism (auto)

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: rs2229521; hg19: chr10-90767482; COSMIC: COSV58238795; COSMIC: COSV58238795;