NM_000043.6:c.580G>A

Variant names:

• chr10-89012010-G-A
• rs56006128
• NM_000043.6:c.580G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000043.6(FAS):​c.580G>A​(p.Glu194Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,886 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: FAS NM_000043.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:8 O:1
• Conservation: PhyloP100: -1.15
• Publications: 15 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061986744).
• BP6: Variant 10-89012010-G-A is Benign according to our data. Variant chr10-89012010-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134374.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00142 (216/152306) while in subpopulation NFE AF = 0.00232 (158/68030). AF 95% confidence interval is 0.00203. There are 0 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR,AD gene

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.580G>A	p.Glu194Lys	missense	Exon 7 of 9	NP_000034.1	P25445-1
	FAS	NM_001410956.1		c.625G>A	p.Glu209Lys	missense	Exon 7 of 9	NP_001397885.1	A0A8Q3SIR6
	FAS	NM_152871.4		c.517G>A	p.Glu173Lys	missense	Exon 6 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.580G>A	p.Glu194Lys	missense	Exon 7 of 9	ENSP00000498466.1	P25445-1
	FAS	ENST00000357339.7	TSL:1	c.517G>A	p.Glu173Lys	missense	Exon 6 of 8	ENSP00000349896.2	P25445-6
	FAS	ENST00000355279.2	TSL:1	c.580G>A	p.Glu194Lys	missense	Exon 7 of 8	ENSP00000347426.2	P25445-7

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00154 AC: 388 AN: 251260 AF XY: 0.00182

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00247

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00177 AC: 2589 AN: 1461580 Hom.: 4 Cov.: 30 AF XY: 0.00186 AC XY: 1350 AN XY: 727110

African (AFR) AF: 0.000388 AC: 13 AN: 33464

American (AMR) AF: 0.00116 AC: 52 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00194 AC: 167 AN: 86252

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53396

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5764

European-Non Finnish (NFE) AF: 0.00193 AC: 2144 AN: 1111808

Other (OTH) AF: 0.00197 AC: 119 AN: 60386

GnomAD4 genome AF: 0.00142 AC: 216 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.00138 AC XY: 103 AN XY: 74474

African (AFR) AF: 0.000313 AC: 13 AN: 41560

American (AMR) AF: 0.00137 AC: 21 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

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

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00232 AC: 158 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00204 Hom.: 0

Bravo AF: 0.00142

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00180 AC: 219

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00403

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	not provided (6)
-	3	2	Autoimmune lymphoproliferative syndrome type 1 (5)
-	1	1	not specified (3)
-	-	1	FAS-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	0.92
DANN	Benign	0.15
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0062	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.49	N
REVEL	Uncertain	0.45
Sift	Benign	0.72	T
Sift4G	Benign	0.62	T
Polyphen		0.011	B
Vest4		0.069
MVP		0.98
MPC		0.24
ClinPred		0.00088	T
Varity_R		0.11
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.080		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: rs56006128; hg19: chr10-90771767; COSMIC: COSV100570917; COSMIC: COSV100570917;