10-88989499-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000690268.1(FAS):c.31G>A(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 543,676 control chromosomes in the GnomAD database, including 6,468 homozygotes. In-silico tool predicts a benign outcome for this variant. 4/4 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1426 hom., cov: 32)
  • Exomes 𝑓: 0.14 (5042 hom.)
• Consequence: FAS ENST00000690268.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.866

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]

ACTA2 (HGNC:130): (actin alpha 2, smooth muscle) This gene encodes one of six different actin proteins. Actins are highly conserved proteins that are involved in cell motility, structure, integrity, and intercellular signaling. The encoded protein is a smooth muscle actin that is involved in vascular contractility and blood pressure homeostasis. Mutations in this gene cause a variety of vascular diseases, such as thoracic aortic disease, coronary artery disease, stroke, and Moyamoya disease, as well as multisystemic smooth muscle dysfunction syndrome. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-88989499-G-A is Benign according to our data. Variant chr10-88989499-G-A is described in ClinVar as [Benign]. Clinvar id is 16517.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAS	XM_011539764.3	c.112G>A	p.Ala38Thr	missense_variant	2/10
FAS	XM_011539765.3	c.112G>A	p.Ala38Thr	missense_variant	2/9
FAS	XM_006717819.4	c.31G>A	p.Ala11Thr	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000690268.1	c.31G>A	p.Ala11Thr	missense_variant	3/11			A2
ACTA2	ENST00000415557.2	c.-24+1440C>T		intron_variant		3		P1
ACTA2	ENST00000458159.6	c.-24+1523C>T		intron_variant		3		P1

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17311 AN: 151962 Hom.: 1428 Cov.: 32

Gnomad AFR AF: 0.0470

Gnomad AMI AF: 0.0658

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.129

GnomAD3 exomes AF: 0.151 AC: 34536 AN: 229260 Hom.: 3511 AF XY: 0.149 AC XY: 18932 AN XY: 126712

Gnomad AFR exome AF: 0.0447

Gnomad AMR exome AF: 0.172

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.425

Gnomad SAS exome AF: 0.176

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.141 AC: 55307 AN: 391596 Hom.: 5042 Cov.: 0 AF XY: 0.142 AC XY: 31435 AN XY: 221656

Gnomad4 AFR exome AF: 0.0480

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.423

Gnomad4 SAS exome AF: 0.171

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.114 AC: 17313 AN: 152080 Hom.: 1426 Cov.: 32 AF XY: 0.118 AC XY: 8766 AN XY: 74356

Gnomad4 AFR AF: 0.0470

Gnomad4 AMR AF: 0.163

Gnomad4 ASJ AF: 0.123

Gnomad4 EAS AF: 0.420

Gnomad4 SAS AF: 0.187

Gnomad4 FIN AF: 0.121

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.130

Alfa AF: 0.111 Hom.: 251

Bravo AF: 0.112

Asia WGS AF: 0.327 AC: 1135 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 33% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported. -

LUNG CANCER, SUSCEPTIBILITY TO Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.31
Dann	Benign	0.50

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2234767; hg19: chr10-90749256; COSMIC: COSV58238613;