rs4934435

Positions:

• chr10-89016639-A-G
• chr10-89016639-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000043.6(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_000043.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.271

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAS	NM_000043.6	c.*2189A>G		3_prime_UTR_variant	9/9	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.*2189A>G		3_prime_UTR_variant	9/9		NM_000043.6	ENSP00000498466	A2

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

Gnomad4 AFR exome AF: 0.678

Gnomad4 AMR exome AF: 0.799

Gnomad4 ASJ exome AF: 0.742

Gnomad4 EAS exome AF: 0.950

Gnomad4 SAS exome AF: 0.824

Gnomad4 FIN exome AF: 0.821

Gnomad4 NFE exome AF: 0.702

Gnomad4 OTH exome AF: 0.737

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

Gnomad4 AFR AF: 0.680

Gnomad4 AMR AF: 0.798

Gnomad4 ASJ AF: 0.747

Gnomad4 EAS AF: 0.974

Gnomad4 SAS AF: 0.819

Gnomad4 FIN AF: 0.793

Gnomad4 NFE AF: 0.704

Gnomad4 OTH AF: 0.742

Alfa AF: 0.730 Hom.: 6890

Bravo AF: 0.724

Asia WGS AF: 0.864 AC: 3004 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs4934435; hg19: chr10-90776396;