3-172523288-C-T

Position:

• chr3-172523288-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003810.4(TNFSF10):​c.97G>A​(p.Val33Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00299 in 1,613,956 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.016 (60 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (60 hom.)
• Consequence: TNFSF10 NM_003810.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.349

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023798048).
• BP6: Variant 3-172523288-C-T is Benign according to our data. Variant chr3-172523288-C-T is described in ClinVar as [Benign]. Clinvar id is 788974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0515 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFSF10	NM_003810.4	c.97G>A	p.Val33Ile	missense_variant	1/5	ENST00000241261.7	NP_003801.1
TNFSF10	NM_001190942.2	c.97G>A	p.Val33Ile	missense_variant	1/3		NP_001177871.1
TNFSF10	NM_001190943.2	c.97G>A	p.Val33Ile	missense_variant	1/2		NP_001177872.1
TNFSF10	NR_033994.2	n.143G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFSF10	ENST00000241261.7	c.97G>A	p.Val33Ile	missense_variant	1/5	1	NM_003810.4	ENSP00000241261	P1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2375 AN: 152184 Hom.: 60 Cov.: 32

Gnomad AFR AF: 0.0534

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00411 AC: 1032 AN: 251046 Hom.: 33 AF XY: 0.00301 AC XY: 409 AN XY: 135676

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.00260

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00168 AC: 2451 AN: 1461654 Hom.: 60 Cov.: 31 AF XY: 0.00145 AC XY: 1053 AN XY: 727152

Gnomad4 AFR exome AF: 0.0571

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000162

Gnomad4 OTH exome AF: 0.00336

GnomAD4 genome AF: 0.0156 AC: 2380 AN: 152302 Hom.: 60 Cov.: 32 AF XY: 0.0154 AC XY: 1149 AN XY: 74472

Gnomad4 AFR AF: 0.0533

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.0196 Hom.: 2369

Bravo AF: 0.0182

ESP6500AA AF: 0.0527 AC: 232

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00504 AC: 612

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 13, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.75	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.48	N;N
REVEL	Benign	0.041
Sift	Benign	0.32	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.062	B;.
Vest4		0.088
MVP		0.39
MPC		0.051
ClinPred		0.020	T
GERP RS		3.8
Varity_R		0.051
gMVP		0.20

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: rs6763816; hg19: chr3-172241078;