Genetic Variant NM_001244.4:c.311-73C>T (chr9-114904398-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001244.4(TNFSF8):c.311-73C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,514,676 control chromosomes in the GnomAD database, including 173,127 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 0.56 ( 25730 hom., cov: 32)

Exomes 𝑓: 0.46 ( 147397 hom. )

Consequence

TNFSF8
NM_001244.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.678

Publications

6 publications found

Variant links:

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]

TNFSF8 links:

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]

DELEC1 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF8	NM_001244.4 link	c.311-73C>T		intron_variant	Intron 3 of 3	ENST00000223795.3	NP_001235.1	P32971Q52M88
TNFSF8	NM_001252290.1 link	c.311-73C>T		intron_variant	Intron 3 of 4		NP_001239219.1	Q52M88A0A087X228

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF8	ENST00000223795.3 link	c.311-73C>T		intron_variant	Intron 3 of 3	1	NM_001244.4	ENSP00000223795.2		P32971

Frequencies

GnomAD3 genomes

AF:

0.562

AC:

85386

AN:

151884

Hom.:

25681

Cov.:

show subpopulations

Gnomad AFR

AF:

0.770

Gnomad AMI

AF:

0.644

Gnomad AMR

AF:

0.644

Gnomad ASJ

AF:

0.461

Gnomad EAS

AF:

0.405

Gnomad SAS

AF:

0.453

Gnomad FIN

AF:

0.504

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.452

Gnomad OTH

AF:

0.523

GnomAD4 exome

AF:

0.458

AC:

624737

AN:

1362674

Hom.:

147397

AF XY:

0.457

AC XY:

305671

AN XY:

669308

show subpopulations

African (AFR)

AF:

0.789

AC:

23854

AN:

30224

American (AMR)

AF:

0.723

AC:

21144

AN:

29250

Ashkenazi Jewish (ASJ)

AF:

0.481

AC:

9662

AN:

20094

East Asian (EAS)

AF:

0.487

AC:

19023

AN:

39022

South Asian (SAS)

AF:

0.446

AC:

30854

AN:

69114

European-Finnish (FIN)

AF:

0.497

AC:

22587

AN:

45484

Middle Eastern (MID)

AF:

0.433

AC:

2163

AN:

5000

European-Non Finnish (NFE)

AF:

0.439

AC:

468977

AN:

1068236

Other (OTH)

AF:

0.471

AC:

26473

AN:

56250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

14214

28427

42641

56854

71068

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.562

AC:

85500

AN:

152002

Hom.:

25730

Cov.:

AF XY:

0.565

AC XY:

42001

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.770

AC:

31944

AN:

41476

American (AMR)

AF:

0.645

AC:

9857

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

1599

AN:

3470

East Asian (EAS)

AF:

0.405

AC:

2089

AN:

5158

South Asian (SAS)

AF:

0.451

AC:

2175

AN:

4820

European-Finnish (FIN)

AF:

0.504

AC:

5321

AN:

10554

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.452

AC:

30698

AN:

67930

Other (OTH)

AF:

0.526

AC:

1109

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1787

3574

5361

7148

8935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.522

Hom.:

3526

Bravo

AF:

0.585

Asia WGS

AF:

0.515

AC:

1783

AN:

3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.69

(source)

DANN

Benign

0.66

PhyloP100

-0.68

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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NM_001244.4:c.311-73C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over