9-114790878-A-T

Position:

• chr9-114790878-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005118.4(TNFSF15):​c.330T>A​(p.Phe110Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00258 in 1,614,128 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.0076 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (38 hom.)
• Consequence: TNFSF15 NM_005118.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.166

Genes affected

TNFSF15 (HGNC:11931): (TNF superfamily member 15) The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein is abundantly expressed in endothelial cells, but is not expressed in either B or T cells. The expression of this protein is inducible by TNF and IL-1 alpha. This cytokine is a ligand for receptor TNFRSF25 and decoy receptor TNFRSF21/DR6. It can activate NF-kappaB and MAP kinases, and acts as an autocrine factor to induce apoptosis in endothelial cells. This cytokine is also found to inhibit endothelial cell proliferation, and thus may function as an angiogenesis inhibitor. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020623207).
• BP6: Variant 9-114790878-A-T is Benign according to our data. Variant chr9-114790878-A-T is described in ClinVar as [Benign]. Clinvar id is 768323.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00757 (1152/152258) while in subpopulation EAS AF= 0.033 (171/5184). AF 95% confidence interval is 0.0289. There are 9 homozygotes in gnomad4. There are 589 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFSF15	NM_005118.4	c.330T>A	p.Phe110Leu	missense_variant	4/4	ENST00000374045.5
TNFSF15	NM_001204344.1	c.153T>A	p.Phe51Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFSF15	ENST00000374045.5	c.330T>A	p.Phe110Leu	missense_variant	4/4	1	NM_005118.4	P1
TNFSF15	ENST00000374044.1	c.99T>A	p.Phe33Leu	missense_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00757 AC: 1152 AN: 152140 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.0204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0331

Gnomad SAS AF: 0.00912

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00566 AC: 1413 AN: 249534 Hom.: 27 AF XY: 0.00547 AC XY: 738 AN XY: 135004

Gnomad AFR exome AF: 0.0189

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.0351

Gnomad SAS exome AF: 0.00980

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.000429

Gnomad OTH exome AF: 0.00344

GnomAD4 exome AF: 0.00206 AC: 3006 AN: 1461870 Hom.: 38 Cov.: 36 AF XY: 0.00216 AC XY: 1569 AN XY: 727232

Gnomad4 AFR exome AF: 0.0203

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0233

Gnomad4 SAS exome AF: 0.00868

Gnomad4 FIN exome AF: 0.00258

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.00432

GnomAD4 genome AF: 0.00757 AC: 1152 AN: 152258 Hom.: 9 Cov.: 31 AF XY: 0.00791 AC XY: 589 AN XY: 74454

Gnomad4 AFR AF: 0.0203

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0330

Gnomad4 SAS AF: 0.00913

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00185 Hom.: 2

Bravo AF: 0.00799

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00609 AC: 739

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

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

Invitae

Apr 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.0
DANN	Benign	0.72
DEOGEN2	Benign	0.049	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.087	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.3	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.73	N;N
REVEL	Benign	0.050
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;.
Vest4		0.034
MutPred		0.13		Loss of methylation at K111 (P = 0.033);.;
MVP		0.38
MPC		0.13
ClinPred		0.0029	T
GERP RS		3.0
Varity_R		0.21
gMVP		0.22

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: rs16931745; hg19: chr9-117553158; COSMIC: COSV65010335;