chr10-89016639-A-G

Variant names:

• chr10-89016639-A-G
• rs4934435
• NM_000043.6:c.*2189A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001410956.1(FAS):​c.*2189A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.733 in 222,538 control chromosomes in the GnomAD database, including 60,526 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.73 (40504 hom., cov: 30)
  • Exomes 𝑓: 0.75 (20022 hom.)
• Consequence: FAS NM_001410956.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.271
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 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.*2189A>G		3_prime_UTR	Exon 9 of 9	NP_000034.1
	FAS	NM_001410956.1		c.*2189A>G		3_prime_UTR	Exon 9 of 9	NP_001397885.1
	FAS	NM_152871.4		c.*2189A>G		3_prime_UTR	Exon 8 of 8	NP_690610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000652046.1	MANE Select	c.*2189A>G		3_prime_UTR	Exon 9 of 9	ENSP00000498466.1
	FAS	ENST00000357339.7	TSL:1	c.*2189A>G		3_prime_UTR	Exon 8 of 8	ENSP00000349896.2
	FAS	ENST00000492756.7	TSL:1	n.*2626A>G		non_coding_transcript_exon	Exon 7 of 7	ENSP00000422453.1

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110406 AN: 151870 Hom.: 40476 Cov.: 30

Gnomad AFR AF: 0.680

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.798

Gnomad ASJ AF: 0.747

Gnomad EAS AF: 0.974

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.793

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.746

GnomAD4 exome AF: 0.747 AC: 52681 AN: 70550 Hom.: 20022 Cov.: 0 AF XY: 0.748 AC XY: 24387 AN XY: 32618

African (AFR) AF: 0.678 AC: 2206 AN: 3254

American (AMR) AF: 0.799 AC: 1678 AN: 2100

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 3332 AN: 4492

East Asian (EAS) AF: 0.950 AC: 9780 AN: 10294

South Asian (SAS) AF: 0.824 AC: 511 AN: 620

European-Finnish (FIN) AF: 0.821 AC: 46 AN: 56

Middle Eastern (MID) AF: 0.740 AC: 330 AN: 446

European-Non Finnish (NFE) AF: 0.702 AC: 30473 AN: 43420

Other (OTH) AF: 0.737 AC: 4325 AN: 5868

GnomAD4 genome AF: 0.727 AC: 110491 AN: 151988 Hom.: 40504 Cov.: 30 AF XY: 0.734 AC XY: 54542 AN XY: 74280

African (AFR) AF: 0.680 AC: 28174 AN: 41422

American (AMR) AF: 0.798 AC: 12208 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.747 AC: 2591 AN: 3468

East Asian (EAS) AF: 0.974 AC: 5041 AN: 5176

South Asian (SAS) AF: 0.819 AC: 3945 AN: 4818

European-Finnish (FIN) AF: 0.793 AC: 8354 AN: 10532

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.704 AC: 47819 AN: 67968

Other (OTH) AF: 0.742 AC: 1564 AN: 2108

Alfa AF: 0.729 Hom.: 7072

Bravo AF: 0.724

Asia WGS AF: 0.864 AC: 3004 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.4
DANN	Benign	0.33
PhyloP100		-0.27

Splicing

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

Other links and lift over

dbSNP: rs4934435; hg19: chr10-90776396;