3-172506513-A-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_003810.4(TNFSF10):c.825T>C(p.Phe275=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.673 in 1,603,922 control chromosomes in the GnomAD database, including 365,230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.69 (36926 hom., cov: 32)
  • Exomes 𝑓: 0.67 (328304 hom.)
• Consequence: TNFSF10 NM_003810.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.430

Genes affected

TNFSF10 (HGNC:11925): (TNF superfamily member 10) The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein preferentially induces apoptosis in transformed and tumor cells, but does not appear to kill normal cells although it is expressed at a significant level in most normal tissues. This protein binds to several members of TNF receptor superfamily including TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4, and possibly also to TNFRSF11B/OPG. The activity of this protein may be modulated by binding to the decoy receptors TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4, and TNFRSF11B/OPG that cannot induce apoptosis. The binding of this protein to its receptors has been shown to trigger the activation of MAPK8/JNK, caspase 8, and caspase 3. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 3-172506513-A-G is Benign according to our data. Variant chr3-172506513-A-G is described in ClinVar as [Benign]. Clinvar id is 1236214.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.43 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFSF10	NM_003810.4	c.825T>C	p.Phe275=	synonymous_variant	5/5	ENST00000241261.7
TNFSF10	NM_001190942.2	c.*371T>C		3_prime_UTR_variant	3/3
TNFSF10	NR_033994.2	n.828T>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFSF10	ENST00000241261.7	c.825T>C	p.Phe275=	synonymous_variant	5/5	1	NM_003810.4	P1
TNFSF10	ENST00000420541.6	c.*371T>C		3_prime_UTR_variant	3/3	1

Frequencies

GnomAD3 genomes AF: 0.693 AC: 105355 AN: 151980 Hom.: 36913 Cov.: 32

Gnomad AFR AF: 0.775

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.726

Gnomad EAS AF: 0.609

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.703

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.707

GnomAD3 exomes AF: 0.654 AC: 158359 AN: 242212 Hom.: 52672 AF XY: 0.659 AC XY: 86211 AN XY: 130798

Gnomad AFR exome AF: 0.780

Gnomad AMR exome AF: 0.469

Gnomad ASJ exome AF: 0.735

Gnomad EAS exome AF: 0.605

Gnomad SAS exome AF: 0.639

Gnomad FIN exome AF: 0.713

Gnomad NFE exome AF: 0.681

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.670 AC: 973361 AN: 1451824 Hom.: 328304 Cov.: 61 AF XY: 0.670 AC XY: 483876 AN XY: 721766

Gnomad4 AFR exome AF: 0.783

Gnomad4 AMR exome AF: 0.480

Gnomad4 ASJ exome AF: 0.735

Gnomad4 EAS exome AF: 0.603

Gnomad4 SAS exome AF: 0.636

Gnomad4 FIN exome AF: 0.712

Gnomad4 NFE exome AF: 0.675

Gnomad4 OTH exome AF: 0.684

GnomAD4 genome AF: 0.693 AC: 105417 AN: 152098 Hom.: 36926 Cov.: 32 AF XY: 0.690 AC XY: 51339 AN XY: 74370

Gnomad4 AFR AF: 0.775

Gnomad4 AMR AF: 0.567

Gnomad4 ASJ AF: 0.726

Gnomad4 EAS AF: 0.609

Gnomad4 SAS AF: 0.631

Gnomad4 FIN AF: 0.703

Gnomad4 NFE AF: 0.677

Gnomad4 OTH AF: 0.704

Alfa AF: 0.663 Hom.: 18956

Bravo AF: 0.685

EpiCase AF: 0.691

EpiControl AF: 0.697

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.19
Dann	Benign	0.42

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: rs1131532; hg19: chr3-172224303; COSMIC: COSV53842647; COSMIC: COSV53842647;