chr10-89010616-C-T

Position:

• chr10-89010616-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000043.6(FAS):​c.505+16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,612,254 control chromosomes in the GnomAD database, including 195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (20 hom., cov: 33)
  • Exomes 𝑓: 0.012 (175 hom.)
• Consequence: FAS NM_000043.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.507

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 10-89010616-C-T is Benign according to our data. Variant chr10-89010616-C-T is described in ClinVar as [Benign]. Clinvar id is 522237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-89010616-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00999 (1519/152098) while in subpopulation NFE AF= 0.0107 (729/67970). AF 95% confidence interval is 0.0101. There are 20 homozygotes in gnomad4. There are 889 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAS	NM_000043.6	c.505+16C>T		intron_variant		ENST00000652046.1	NP_000034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAS	ENST00000652046.1	c.505+16C>T		intron_variant			NM_000043.6	ENSP00000498466.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1520 AN: 151982 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00498

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00991 AC: 2489 AN: 251154 Hom.: 26 AF XY: 0.00997 AC XY: 1353 AN XY: 135740

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00423

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.0471

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00915

GnomAD4 exome AF: 0.0120 AC: 17464 AN: 1460156 Hom.: 175 Cov.: 31 AF XY: 0.0116 AC XY: 8423 AN XY: 726500

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00443

Gnomad4 ASJ exome AF: 0.000728

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.0436

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0103

GnomAD4 genome AF: 0.00999 AC: 1519 AN: 152098 Hom.: 20 Cov.: 33 AF XY: 0.0120 AC XY: 889 AN XY: 74336

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00498

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0577

Gnomad4 NFE AF: 0.0107

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00444 Hom.: 0

Bravo AF: 0.00617

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autoimmune lymphoproliferative syndrome type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Apr 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.2
DANN	Benign	0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs3218620; hg19: chr10-90770373; COSMIC: COSV58239114; COSMIC: COSV58239114;