19-6534717-G-C

Variant names:

• chr19-6534717-G-C
• rs61750000
• NM_003811.4:c.416G>C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003811.4(TNFSF9):​c.416G>C​(p.Gly139Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,597,264 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0038 (15 hom.)
• Consequence: TNFSF9 NM_003811.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.07

Genes affected

TNFSF9 (HGNC:11939): (TNF superfamily member 9) The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This transmembrane cytokine is a bidirectional signal transducer that acts as a ligand for TNFRSF9/4-1BB, which is a costimulatory receptor molecule in T lymphocytes. This cytokine and its receptor are involved in the antigen presentation process and in the generation of cytotoxic T cells. The receptor TNFRSF9/4-1BB is absent from resting T lymphocytes but rapidly expressed upon antigenic stimulation. The ligand encoded by this gene, TNFSF9/4-1BBL, has been shown to reactivate anergic T lymphocytes in addition to promoting T lymphocyte proliferation. This cytokine has also been shown to be required for the optimal CD8 responses in CD8 T cells. This cytokine is expressed in carcinoma cell lines, and is thought to be involved in T cell-tumor cell interaction.[provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03439164).
• BP6: Variant 19-6534717-G-C is Benign according to our data. Variant chr19-6534717-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 716716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF9	NM_003811.4	c.416G>C	p.Gly139Ala	missense_variant	Exon 3 of 3	ENST00000245817.5	NP_003802.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF9	ENST00000245817.5	c.416G>C	p.Gly139Ala	missense_variant	Exon 3 of 3	1	NM_003811.4	ENSP00000245817.2

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 422 AN: 152152 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00525

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00227 AC: 497 AN: 218846 Hom.: 0 AF XY: 0.00242 AC XY: 287 AN XY: 118708

Gnomad AFR exome AF: 0.000734

Gnomad AMR exome AF: 0.000643

Gnomad ASJ exome AF: 0.000320

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000107

Gnomad NFE exome AF: 0.00467

Gnomad OTH exome AF: 0.00202

GnomAD4 exome AF: 0.00375 AC: 5421 AN: 1444994 Hom.: 15 Cov.: 31 AF XY: 0.00363 AC XY: 2604 AN XY: 717452

Gnomad4 AFR exome AF: 0.000784

Gnomad4 AMR exome AF: 0.000905

Gnomad4 ASJ exome AF: 0.000427

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000175

Gnomad4 NFE exome AF: 0.00471

Gnomad4 OTH exome AF: 0.00231

GnomAD4 genome AF: 0.00277 AC: 422 AN: 152270 Hom.: 1 Cov.: 30 AF XY: 0.00248 AC XY: 185 AN XY: 74454

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00525

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00439 Hom.: 1

Bravo AF: 0.00278

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000914 AC: 4

ESP6500EA AF: 0.00489 AC: 42

ExAC AF: 0.00198 AC: 238

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 28, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.034	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.66
MVP		0.89
MPC		0.24
ClinPred		0.092	T
GERP RS		4.1
Varity_R		0.91
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs61750000; hg19: chr19-6534728; COSMIC: COSV99832500;