rs2296600

Variant names:

• chr10-89010682-C-G
• rs2296600
• NM_000043.6:c.506-71C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-89010682-C-G
• chr10-89010682-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000043.6(FAS):​c.506-71C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.4 in 1,605,568 control chromosomes in the GnomAD database, including 130,037 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11402 hom., cov: 32)
  • Exomes 𝑓: 0.40 (118635 hom.)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.557
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-89010682-C-G is Benign according to our data. Variant chr10-89010682-C-G is described in ClinVar as Benign. ClinVar VariationId is 1291170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6	c.506-71C>G		intron_variant	Intron 5 of 8	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.506-71C>G		intron_variant	Intron 5 of 8		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58543 AN: 151898 Hom.: 11403 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.436

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.404

GnomAD4 exome AF: 0.402 AC: 583941 AN: 1453550 Hom.: 118635 Cov.: 29 AF XY: 0.404 AC XY: 292301 AN XY: 723764

African (AFR) AF: 0.340 AC: 11320 AN: 33276

American (AMR) AF: 0.352 AC: 15713 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 12440 AN: 26082

East Asian (EAS) AF: 0.484 AC: 19165 AN: 39616

South Asian (SAS) AF: 0.458 AC: 39465 AN: 86090

European-Finnish (FIN) AF: 0.414 AC: 22065 AN: 53342

Middle Eastern (MID) AF: 0.456 AC: 2628 AN: 5760

European-Non Finnish (NFE) AF: 0.395 AC: 436369 AN: 1104618

Other (OTH) AF: 0.412 AC: 24776 AN: 60104

GnomAD4 genome AF: 0.385 AC: 58550 AN: 152018 Hom.: 11402 Cov.: 32 AF XY: 0.389 AC XY: 28941 AN XY: 74320

African (AFR) AF: 0.333 AC: 13796 AN: 41456

American (AMR) AF: 0.376 AC: 5743 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1675 AN: 3472

East Asian (EAS) AF: 0.503 AC: 2605 AN: 5180

South Asian (SAS) AF: 0.457 AC: 2200 AN: 4818

European-Finnish (FIN) AF: 0.409 AC: 4318 AN: 10546

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.395 AC: 26853 AN: 67958

Other (OTH) AF: 0.401 AC: 848 AN: 2114

Alfa AF: 0.268 Hom.: 669

Bravo AF: 0.382

Asia WGS AF: 0.422 AC: 1464 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 68% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.49
DANN	Benign	0.62
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2296600; hg19: chr10-90770439; COSMIC: COSV58238139; COSMIC: COSV58238139;