3-172514990-G-T

Variant names:

• chr3-172514990-G-T
• rs16845759
• NM_003810.4:c.141C>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003810.4(TNFSF10):​c.141C>A​(p.Asp47Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00656 in 1,614,012 control chromosomes in the GnomAD database, including 438 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.030 (242 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (196 hom.)
• Consequence: TNFSF10 NM_003810.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.393

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012619793).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF10	NM_003810.4	c.141C>A	p.Asp47Glu	missense_variant	Exon 2 of 5	ENST00000241261.7	NP_003801.1
TNFSF10	NM_001190942.2	c.141C>A	p.Asp47Glu	missense_variant	Exon 2 of 3		NP_001177871.1
TNFSF10	NR_033994.2	n.187C>A		non_coding_transcript_exon_variant	Exon 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF10	ENST00000241261.7	c.141C>A	p.Asp47Glu	missense_variant	Exon 2 of 5	1	NM_003810.4	ENSP00000241261.2

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4632 AN: 152070 Hom.: 241 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00989 AC: 2486 AN: 251310 Hom.: 97 AF XY: 0.00763 AC XY: 1037 AN XY: 135832

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.00674

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.00147

Gnomad SAS exome AF: 0.00843

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000836

Gnomad OTH exome AF: 0.00570

GnomAD4 exome AF: 0.00407 AC: 5951 AN: 1461824 Hom.: 196 Cov.: 31 AF XY: 0.00376 AC XY: 2735 AN XY: 727224

Gnomad4 AFR exome AF: 0.0992

Gnomad4 AMR exome AF: 0.00725

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.000705

Gnomad4 SAS exome AF: 0.00800

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000532

Gnomad4 OTH exome AF: 0.00899

GnomAD4 genome AF: 0.0305 AC: 4641 AN: 152188 Hom.: 242 Cov.: 32 AF XY: 0.0288 AC XY: 2146 AN XY: 74424

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.0128

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.00628 Hom.: 82

Bravo AF: 0.0345

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0980 AC: 432

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.0116 AC: 1407

Asia WGS AF: 0.0180 AC: 62 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.00119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.72
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.050	N;N
REVEL	Benign	0.037
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;.
Vest4		0.012
MutPred		0.11		Gain of ubiquitination at K43 (P = 0.0628);Gain of ubiquitination at K43 (P = 0.0628);
MPC		0.054
ClinPred		0.0027	T
GERP RS		-1.5
Varity_R		0.034
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs16845759; hg19: chr3-172232780;