rs2234978

Variant names:

• chr10-89012072-T-C
• rs2234978
• NM_000043.6:c.642T>C
• FAS p.Thr214Thr

Your query was ambiguous. Multiple possible variants found:

• chr10-89012072-T-C
• chr10-89012072-T-G
• chr10-89012072-T-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.642T>C​(p.Thr214Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.727 in 1,611,060 control chromosomes in the GnomAD database, including 428,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T214T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.73 (40584 hom., cov: 33)
  • Exomes 𝑓: 0.73 (388317 hom.)
• Consequence: FAS NM_000043.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: -0.710
• Publications: 88 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: Orphanet, G2P
• 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=-0.96).
• BP6: Variant 10-89012072-T-C is Benign according to our data. Variant chr10-89012072-T-C is described in ClinVar as Benign. ClinVar VariationId is 254734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

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.642T>C	p.Thr214Thr	synonymous	Exon 7 of 9	NP_000034.1	P25445-1
	FAS	NM_001410956.1		c.687T>C	p.Thr229Thr	synonymous	Exon 7 of 9	NP_001397885.1	A0A8Q3SIR6
	FAS	NM_152871.4		c.579T>C	p.Thr193Thr	synonymous	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.642T>C	p.Thr214Thr	synonymous	Exon 7 of 9	ENSP00000498466.1	P25445-1
	FAS	ENST00000357339.7	TSL:1	c.579T>C	p.Thr193Thr	synonymous	Exon 6 of 8	ENSP00000349896.2	P25445-6
	FAS	ENST00000355279.2	TSL:1	c.642T>C	p.Thr214Thr	synonymous	Exon 7 of 8	ENSP00000347426.2	P25445-7

Frequencies

GnomAD3 genomes AF: 0.727 AC: 110589 AN: 152056 Hom.: 40556 Cov.: 33

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.636

Gnomad AMR AF: 0.798

Gnomad ASJ AF: 0.748

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.819

Gnomad FIN AF: 0.794

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.704

Gnomad OTH AF: 0.746

GnomAD2 exomes AF: 0.766 AC: 192259 AN: 251130 AF XY: 0.763

Gnomad AFR exome AF: 0.676

Gnomad AMR exome AF: 0.857

Gnomad ASJ exome AF: 0.733

Gnomad EAS exome AF: 0.983

Gnomad FIN exome AF: 0.789

Gnomad NFE exome AF: 0.699

Gnomad OTH exome AF: 0.748

GnomAD4 exome AF: 0.727 AC: 1060736 AN: 1458886 Hom.: 388317 Cov.: 35 AF XY: 0.729 AC XY: 529531 AN XY: 725916

African (AFR) AF: 0.677 AC: 22619 AN: 33406

American (AMR) AF: 0.847 AC: 37865 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 19244 AN: 26098

East Asian (EAS) AF: 0.962 AC: 38167 AN: 39668

South Asian (SAS) AF: 0.820 AC: 70685 AN: 86198

European-Finnish (FIN) AF: 0.787 AC: 41981 AN: 53372

Middle Eastern (MID) AF: 0.730 AC: 4202 AN: 5756

European-Non Finnish (NFE) AF: 0.704 AC: 781409 AN: 1109402

Other (OTH) AF: 0.739 AC: 44564 AN: 60302

GnomAD4 genome AF: 0.727 AC: 110674 AN: 152174 Hom.: 40584 Cov.: 33 AF XY: 0.735 AC XY: 54652 AN XY: 74400

African (AFR) AF: 0.681 AC: 28262 AN: 41506

American (AMR) AF: 0.799 AC: 12220 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.748 AC: 2593 AN: 3468

East Asian (EAS) AF: 0.974 AC: 5051 AN: 5188

South Asian (SAS) AF: 0.819 AC: 3951 AN: 4826

European-Finnish (FIN) AF: 0.794 AC: 8404 AN: 10582

Middle Eastern (MID) AF: 0.731 AC: 215 AN: 294

European-Non Finnish (NFE) AF: 0.704 AC: 47833 AN: 67990

Other (OTH) AF: 0.742 AC: 1565 AN: 2110

Alfa AF: 0.713 Hom.: 194384

Bravo AF: 0.724

Asia WGS AF: 0.864 AC: 3005 AN: 3478

EpiCase AF: 0.695

EpiControl AF: 0.699

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Autoimmune lymphoproliferative syndrome type 1 (3)
-	-	2	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.1
DANN	Benign	0.50
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2234978;

hg19: chr10-90771829;

COSMIC: COSV108108887;

COSMIC: COSV108108887;