rs3218613

Variant names:

• chr10-89003181-G-A
• rs3218613
• NM_000043.6:c.183G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001410956.1(FAS):​c.228G>A​(p.Lys76Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00902 in 1,614,074 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (85 hom.)
• Consequence: FAS NM_001410956.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: -0.0350
• Publications: 7 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=-0.84).
• BP6: Variant 10-89003181-G-A is Benign according to our data. Variant chr10-89003181-G-A is described in ClinVar as Benign. ClinVar VariationId is 155871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.035 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00598 (910/152294) while in subpopulation NFE AF = 0.0104 (710/68016). AF 95% confidence interval is 0.0098. There are 4 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

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.183G>A	p.Lys61Lys	synonymous	Exon 2 of 9	NP_000034.1
	FAS	NM_001410956.1		c.228G>A	p.Lys76Lys	synonymous	Exon 2 of 9	NP_001397885.1
	FAS	NM_152871.4		c.183G>A	p.Lys61Lys	synonymous	Exon 2 of 8	NP_690610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000652046.1	MANE Select	c.183G>A	p.Lys61Lys	synonymous	Exon 2 of 9	ENSP00000498466.1
	FAS	ENST00000357339.7	TSL:1	c.183G>A	p.Lys61Lys	synonymous	Exon 2 of 8	ENSP00000349896.2
	FAS	ENST00000355279.2	TSL:1	c.183G>A	p.Lys61Lys	synonymous	Exon 2 of 8	ENSP00000347426.2

Frequencies

GnomAD3 genomes AF: 0.00599 AC: 911 AN: 152176 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00656 AC: 1649 AN: 251422 AF XY: 0.00710

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00531

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00934 AC: 13653 AN: 1461780 Hom.: 85 Cov.: 31 AF XY: 0.00931 AC XY: 6768 AN XY: 727194

African (AFR) AF: 0.00117 AC: 39 AN: 33474

American (AMR) AF: 0.00116 AC: 52 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39696

South Asian (SAS) AF: 0.00845 AC: 729 AN: 86256

European-Finnish (FIN) AF: 0.00565 AC: 302 AN: 53412

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0109 AC: 12067 AN: 1111932

Other (OTH) AF: 0.00729 AC: 440 AN: 60388

GnomAD4 genome AF: 0.00598 AC: 910 AN: 152294 Hom.: 4 Cov.: 32 AF XY: 0.00533 AC XY: 397 AN XY: 74468

African (AFR) AF: 0.00149 AC: 62 AN: 41572

American (AMR) AF: 0.00275 AC: 42 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4828

European-Finnish (FIN) AF: 0.00518 AC: 55 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0104 AC: 710 AN: 68016

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00797 Hom.: 5

Bravo AF: 0.00527

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00954

EpiControl AF: 0.00871

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	2	Autoimmune lymphoproliferative syndrome type 1 (3)
-	-	3	not provided (3)
-	-	1	FAS-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.49
DANN	Benign	0.32
PhyloP100		-0.035
Mutation Taster		=100/0	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: rs3218613; hg19: chr10-90762938; COSMIC: COSV58240019;