rs761018648

Variant names:

• chr9-114930279-G-A
• rs761018648
• NM_001244.4:c.25C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-114930279-G-A
• chr9-114930279-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001244.4(TNFSF8):​c.25C>T​(p.Leu9Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,438,664 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. L9V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000011 (1 hom.)
• Consequence: TNFSF8 NM_001244.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0370
• Publications: 1 publications found

Genes affected

TNFSF8 (HGNC:11938): (TNF superfamily member 8) The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This cytokine is a ligand for TNFRSF8/CD30, which is a cell surface antigen and a marker for Hodgkin lymphoma and related hematologic malignancies. The engagement of this cytokine expressed on B cell surface plays an inhibitory role in modulating Ig class switch. This cytokine was shown to enhance cell proliferation of some lymphoma cell lines, while to induce cell death and reduce cell proliferation of other lymphoma cell lines. The pleiotropic biologic activities of this cytokine on different CD30+ lymphoma cell lines may play a pathophysiologic role in Hodgkin's and some non-Hodgkin's lymphomas. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

DELEC1 (HGNC:23658): (deleted in esophageal cancer 1) The function of this gene is not known. This gene is located in a region commonly deleted in esophageal squamous cell carcinomas. Gene expression is reduced or absent in these carcinomas and thus this is a candidate tumor suppressor gene for esophageal squamous cell carcinomas. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07448378).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001244.4. 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
	TNFSF8	NM_001244.4	MANE Select	c.25C>T	p.Leu9Phe	missense	Exon 1 of 4	NP_001235.1	P32971
	TNFSF8	NM_001252290.1		c.25C>T	p.Leu9Phe	missense	Exon 1 of 5	NP_001239219.1	A0A087X228

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF8	ENST00000223795.3	TSL:1 MANE Select	c.25C>T	p.Leu9Phe	missense	Exon 1 of 4	ENSP00000223795.2	P32971
	TNFSF8	ENST00000872160.1		c.25C>T	p.Leu9Phe	missense	Exon 1 of 3	ENSP00000542219.1
	TNFSF8	ENST00000618336.4	TSL:3	c.25C>T	p.Leu9Phe	missense	Exon 1 of 5	ENSP00000484651.1	A0A087X228

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000438 AC: 1 AN: 228094 AF XY: 0.00000807

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1438664 Hom.: 1 Cov.: 30 AF XY: 0.0000140 AC XY: 10 AN XY: 715674

African (AFR) AF: 0.00 AC: 0 AN: 32130

American (AMR) AF: 0.00 AC: 0 AN: 41156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25320

East Asian (EAS) AF: 0.00 AC: 0 AN: 37702

South Asian (SAS) AF: 0.000191 AC: 16 AN: 83708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5364

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1100896

Other (OTH) AF: 0.00 AC: 0 AN: 59342

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.074	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.037
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.045
Sift	Benign	0.13	T
Sift4G	Benign	0.17	T
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.12		Loss of helix (P = 0.1299)
MVP		0.043
MPC		0.25
ClinPred		0.048	T
GERP RS		0.84
PromoterAI		0.0070	Neutral
Varity_R		0.11
gMVP		0.30
Mutation Taster		=96/4	polymorphism

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: rs761018648; hg19: chr9-117692559; COSMIC: COSV99802042;