chr9-114790969-T-C

Variant names:

• chr9-114790969-T-C
• rs4246905
• NM_005118.4:c.302-63A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005118.4(TNFSF15):​c.302-63A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 1,539,120 control chromosomes in the GnomAD database, including 419,605 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.79 (48111 hom., cov: 31)
  • Exomes 𝑓: 0.73 (371494 hom.)
• Consequence: TNFSF15 NM_005118.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.671
• Publications: 75 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.2134983E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005118.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF15	NM_005118.4	MANE Select	c.302-63A>G		intron	N/A	NP_005109.2
	TNFSF15	NM_001204344.1		c.125-63A>G		intron	N/A	NP_001191273.1	O95150-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF15	ENST00000374045.5	TSL:1 MANE Select	c.302-63A>G		intron	N/A	ENSP00000363157.3	O95150-1
	TNFSF15	ENST00000374044.1	TSL:6	c.8A>G	p.His3Arg	missense	Exon 1 of 1	ENSP00000363156.1	X6R8I9

Frequencies

GnomAD3 genomes AF: 0.790 AC: 120037 AN: 152024 Hom.: 48036 Cov.: 31

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.811

Gnomad AMR AF: 0.791

Gnomad ASJ AF: 0.759

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.771

Gnomad FIN AF: 0.808

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.716

Gnomad OTH AF: 0.755

GnomAD2 exomes AF: 0.761 AC: 170804 AN: 224406 AF XY: 0.754

Gnomad AFR exome AF: 0.933

Gnomad AMR exome AF: 0.829

Gnomad ASJ exome AF: 0.755

Gnomad EAS exome AF: 0.629

Gnomad FIN exome AF: 0.813

Gnomad NFE exome AF: 0.727

Gnomad OTH exome AF: 0.739

GnomAD4 exome AF: 0.731 AC: 1013359 AN: 1386978 Hom.: 371494 Cov.: 21 AF XY: 0.731 AC XY: 505109 AN XY: 691204

African (AFR) AF: 0.937 AC: 29396 AN: 31362

American (AMR) AF: 0.820 AC: 33713 AN: 41114

Ashkenazi Jewish (ASJ) AF: 0.755 AC: 18649 AN: 24688

East Asian (EAS) AF: 0.683 AC: 26662 AN: 39050

South Asian (SAS) AF: 0.767 AC: 62992 AN: 82086

European-Finnish (FIN) AF: 0.807 AC: 42498 AN: 52642

Middle Eastern (MID) AF: 0.761 AC: 4213 AN: 5538

European-Non Finnish (NFE) AF: 0.715 AC: 752346 AN: 1052922

Other (OTH) AF: 0.745 AC: 42890 AN: 57576

GnomAD4 genome AF: 0.790 AC: 120173 AN: 152142 Hom.: 48111 Cov.: 31 AF XY: 0.794 AC XY: 59025 AN XY: 74380

African (AFR) AF: 0.929 AC: 38566 AN: 41532

American (AMR) AF: 0.791 AC: 12110 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 2631 AN: 3468

East Asian (EAS) AF: 0.649 AC: 3354 AN: 5164

South Asian (SAS) AF: 0.773 AC: 3719 AN: 4812

European-Finnish (FIN) AF: 0.808 AC: 8553 AN: 10586

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.716 AC: 48687 AN: 67964

Other (OTH) AF: 0.756 AC: 1595 AN: 2110

Alfa AF: 0.751 Hom.: 84947

Bravo AF: 0.791

TwinsUK AF: 0.706 AC: 2616

ALSPAC AF: 0.704 AC: 2713

ExAC AF: 0.751 AC: 90787

Asia WGS AF: 0.774 AC: 2689 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.15
DANN	Benign	0.72
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.19	T
MetaRNN	Benign	8.2e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.67
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.0
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.021
ClinPred		0.0032	T
GERP RS		-4.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4246905; hg19: chr9-117553249; COSMIC: COSV65010019;