10-88991225-T-G

Position:

• chr10-88991225-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000043.6(FAS):​c.30+319T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.886 in 524,120 control chromosomes in the GnomAD database, including 206,463 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (62201 hom., cov: 32)
  • Exomes 𝑓: 0.88 (144262 hom.)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.104

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]

ENSG00000286116 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 10-88991225-T-G is Benign according to our data. Variant chr10-88991225-T-G is described in ClinVar as [Benign]. Clinvar id is 1229597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.971 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAS	NM_000043.6	c.30+319T>G		intron_variant		ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.30+319T>G		intron_variant			NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.902 AC: 137224 AN: 152096 Hom.: 62135 Cov.: 32

Gnomad AFR AF: 0.974

Gnomad AMI AF: 0.900

Gnomad AMR AF: 0.904

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.850

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.863

Gnomad OTH AF: 0.899

GnomAD4 exome AF: 0.880 AC: 327187 AN: 371906 Hom.: 144262 Cov.: 2 AF XY: 0.879 AC XY: 172702 AN XY: 196566

Gnomad4 AFR exome AF: 0.970

Gnomad4 AMR exome AF: 0.905

Gnomad4 ASJ exome AF: 0.871

Gnomad4 EAS exome AF: 0.994

Gnomad4 SAS exome AF: 0.881

Gnomad4 FIN exome AF: 0.854

Gnomad4 NFE exome AF: 0.863

Gnomad4 OTH exome AF: 0.885

GnomAD4 genome AF: 0.902 AC: 137351 AN: 152214 Hom.: 62201 Cov.: 32 AF XY: 0.903 AC XY: 67235 AN XY: 74420

Gnomad4 AFR AF: 0.974

Gnomad4 AMR AF: 0.904

Gnomad4 ASJ AF: 0.864

Gnomad4 EAS AF: 0.994

Gnomad4 SAS AF: 0.888

Gnomad4 FIN AF: 0.850

Gnomad4 NFE AF: 0.863

Gnomad4 OTH AF: 0.901

Alfa AF: 0.880 Hom.: 11895

Bravo AF: 0.909

Asia WGS AF: 0.950 AC: 3303 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

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 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 94. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.0
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs7079111; hg19: chr10-90750982;