chr9-114930180-T-G

Variant names:

• chr9-114930180-T-G
• rs577547653
• NM_001244.4:c.124A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001244.4(TNFSF8):​c.124A>C​(p.Thr42Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000048 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TNFSF8 NM_001244.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.69

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF8	NM_001244.4	c.124A>C	p.Thr42Pro	missense_variant	Exon 1 of 4	ENST00000223795.3	NP_001235.1
TNFSF8	NM_001252290.1	c.124A>C	p.Thr42Pro	missense_variant	Exon 1 of 5		NP_001239219.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF8	ENST00000223795.3	c.124A>C	p.Thr42Pro	missense_variant	Exon 1 of 4	1	NM_001244.4	ENSP00000223795.2
TNFSF8	ENST00000618336.4	c.124A>C	p.Thr42Pro	missense_variant	Exon 1 of 5	3		ENSP00000484651.1
DELEC1	ENST00000648852.1	n.198+8582T>G		intron_variant	Intron 2 of 5
DELEC1	ENST00000649565.1	n.226-39404T>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000483 AC: 7 AN: 1450608 Hom.: 0 Cov.: 30 AF XY: 0.00000554 AC XY: 4 AN XY: 721512

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.000379 AC: 46

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.6	.;D
REVEL	Benign	0.17
Sift	Benign	0.059	.;T
Sift4G	Uncertain	0.052	T;T
Polyphen		0.91	.;P
Vest4		0.63
MVP		0.18
MPC		0.83
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.78
gMVP		0.57

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: rs577547653; hg19: chr9-117692460;