10-89008986-C-T

Variant names:

• chr10-89008986-C-T
• rs574338716
• NM_000043.6:c.432C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_000043.6(FAS):​c.432C>T​(p.Asp144Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: FAS NM_000043.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.25
• 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 type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autoimmune lymphoproliferative syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 10-89008986-C-T is Benign according to our data. Variant chr10-89008986-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 301528.
• BP7: Synonymous conserved (PhyloP=-2.25 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000043.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	NM_000043.6	MANE Select	c.432C>T	p.Asp144Asp	synonymous	Exon 4 of 9	NP_000034.1	P25445-1
	FAS	NM_001410956.1		c.477C>T	p.Asp159Asp	synonymous	Exon 4 of 9	NP_001397885.1	A0A8Q3SIR6
	FAS	NM_152871.4		c.432C>T	p.Asp144Asp	synonymous	Exon 4 of 8	NP_690610.1	P25445-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000652046.1	MANE Select	c.432C>T	p.Asp144Asp	synonymous	Exon 4 of 9	ENSP00000498466.1	P25445-1
	FAS	ENST00000357339.7	TSL:1	c.432C>T	p.Asp144Asp	synonymous	Exon 4 of 8	ENSP00000349896.2	P25445-6
	FAS	ENST00000355279.2	TSL:1	c.432C>T	p.Asp144Asp	synonymous	Exon 4 of 8	ENSP00000347426.2	P25445-7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251390 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460726 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726730

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111002

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Autoimmune lymphoproliferative syndrome type 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	5.4
DANN	Benign	0.63
PhyloP100		-2.3

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: rs574338716; hg19: chr10-90768743;