10-89008919-C-T

Variant names:

• chr10-89008919-C-T
• rs3218614
• NM_000043.6:c.365C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000043.6(FAS):​c.365C>T​(p.Thr122Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,613,942 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0076 (14 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (15 hom.)
• Consequence: FAS NM_000043.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.351
• Publications: 18 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000043.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.007054776).
• BP6: Variant 10-89008919-C-T is Benign according to our data. Variant chr10-89008919-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00762 (1161/152270) while in subpopulation AFR AF = 0.0262 (1089/41534). AF 95% confidence interval is 0.0249. There are 14 homozygotes in GnomAd4. There are 534 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AD,AR 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	NM_000043.6	MANE Select	c.365C>T	p.Thr122Ile	missense	Exon 4 of 9	NP_000034.1
	FAS	NM_001410956.1		c.410C>T	p.Thr137Ile	missense	Exon 4 of 9	NP_001397885.1
	FAS	NM_152871.4		c.365C>T	p.Thr122Ile	missense	Exon 4 of 8	NP_690610.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAS	ENST00000652046.1	MANE Select	c.365C>T	p.Thr122Ile	missense	Exon 4 of 9	ENSP00000498466.1
	FAS	ENST00000357339.7	TSL:1	c.365C>T	p.Thr122Ile	missense	Exon 4 of 8	ENSP00000349896.2
	FAS	ENST00000355279.2	TSL:1	c.365C>T	p.Thr122Ile	missense	Exon 4 of 8	ENSP00000347426.2

Frequencies

GnomAD3 genomes AF: 0.00760 AC: 1157 AN: 152152 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0262

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00207 AC: 520 AN: 251456 AF XY: 0.00155

Gnomad AFR exome AF: 0.0271

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000820 AC: 1198 AN: 1461672 Hom.: 15 Cov.: 31 AF XY: 0.000707 AC XY: 514 AN XY: 727148

African (AFR) AF: 0.0259 AC: 865 AN: 33456

American (AMR) AF: 0.00145 AC: 65 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000130 AC: 145 AN: 1111846

Other (OTH) AF: 0.00184 AC: 111 AN: 60386

GnomAD4 genome AF: 0.00762 AC: 1161 AN: 152270 Hom.: 14 Cov.: 32 AF XY: 0.00717 AC XY: 534 AN XY: 74460

African (AFR) AF: 0.0262 AC: 1089 AN: 41534

American (AMR) AF: 0.00314 AC: 48 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68026

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00266 Hom.: 11

Bravo AF: 0.00896

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0268 AC: 118

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00246 AC: 299

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 30, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Autoimmune lymphoproliferative syndrome type 1 Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0071	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.35
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.34
Sift	Benign	0.061	T
Sift4G	Benign	0.095	T
Polyphen		0.93	P
Vest4		0.15
MVP		0.61
MPC		0.49
ClinPred		0.044	T
GERP RS		1.3
Varity_R		0.11
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs3218614; hg19: chr10-90768676;