chr10-89013442-G-A

Variant names:

• chr10-89013442-G-A
• rs3218615
• NM_000043.6:c.676+75G>A

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.676+75G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00628 in 1,370,322 control chromosomes in the GnomAD database, including 414 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (235 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (179 hom.)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.75
• Publications: 3 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=-0.86).
• BP6: Variant 10-89013442-G-A is Benign according to our data. Variant chr10-89013442-G-A is described in ClinVar as Benign. ClinVar VariationId is 1260973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAS	NM_000043.6	c.676+75G>A		intron_variant	Intron 8 of 8	ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.676+75G>A		intron_variant	Intron 8 of 8		NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.0299 AC: 4554 AN: 152054 Hom.: 236 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.00332 AC: 4049 AN: 1218150 Hom.: 179 AF XY: 0.00286 AC XY: 1769 AN XY: 617574

African (AFR) AF: 0.107 AC: 3016 AN: 28298

American (AMR) AF: 0.00654 AC: 281 AN: 42960

Ashkenazi Jewish (ASJ) AF: 0.0000410 AC: 1 AN: 24376

East Asian (EAS) AF: 0.00 AC: 0 AN: 38304

South Asian (SAS) AF: 0.000154 AC: 12 AN: 78014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50666

Middle Eastern (MID) AF: 0.00976 AC: 51 AN: 5224

European-Non Finnish (NFE) AF: 0.000326 AC: 293 AN: 898028

Other (OTH) AF: 0.00756 AC: 395 AN: 52280

GnomAD4 genome AF: 0.0300 AC: 4563 AN: 152172 Hom.: 235 Cov.: 32 AF XY: 0.0290 AC XY: 2158 AN XY: 74400

African (AFR) AF: 0.104 AC: 4311 AN: 41482

American (AMR) AF: 0.0109 AC: 166 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 67998

Other (OTH) AF: 0.0194 AC: 41 AN: 2110

Alfa AF: 0.00789 Hom.: 51

Bravo AF: 0.0343

Asia WGS AF: 0.00696 AC: 24 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.13
DANN	Benign	0.73
PhyloP100		-1.8
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: rs3218615; hg19: chr10-90773199;