10-88991152-C-T

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+246C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 602,490 control chromosomes in the GnomAD database, including 42,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8861 hom., cov: 33)
  • Exomes 𝑓: 0.38 (33956 hom.)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.43

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]

(HGNC:):

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 10-88991152-C-T is Benign according to our data. Variant chr10-88991152-C-T is described in ClinVar as [Benign]. Clinvar id is 1284170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAS	NM_000043.6	c.30+246C>T		intron_variant		ENST00000652046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAS	ENST00000652046.1	c.30+246C>T		intron_variant			NM_000043.6	A2
	ENST00000651408.1	n.3098G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.329 AC: 49998 AN: 152022 Hom.: 8861 Cov.: 33

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.349

GnomAD4 exome AF: 0.383 AC: 172612 AN: 450350 Hom.: 33956 Cov.: 4 AF XY: 0.389 AC XY: 93196 AN XY: 239662

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.352

Gnomad4 ASJ exome AF: 0.429

Gnomad4 EAS exome AF: 0.499

Gnomad4 SAS exome AF: 0.452

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.366

Gnomad4 OTH exome AF: 0.377

GnomAD4 genome AF: 0.329 AC: 50002 AN: 152140 Hom.: 8861 Cov.: 33 AF XY: 0.334 AC XY: 24818 AN XY: 74390

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.521

Gnomad4 SAS AF: 0.442

Gnomad4 FIN AF: 0.381

Gnomad4 NFE AF: 0.366

Gnomad4 OTH AF: 0.347

Alfa AF: 0.351 Hom.: 1222

Bravo AF: 0.320

Asia WGS AF: 0.407 AC: 1415 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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 62% of patients studied by a panel of primary immunodeficiencies. Number of patients: 59. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	4.2
Dann	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12775501; hg19: chr10-90750909;