Genetic Variant TNFRSF10A:c.703+12A>G (chr8-23200675-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003844.4(TNFRSF10A):c.703+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,609,744 control chromosomes in the GnomAD database, including 71,866 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 7284 hom., cov: 31)

Exomes 𝑓: 0.29 ( 64582 hom. )

Consequence

TNFRSF10A
NM_003844.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0290

Publications

28 publications found

Variant links:

Genes affected

TNFRSF10A (HGNC:11904): (TNF receptor superfamily member 10a) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL), and thus transduces cell death signal and induces cell apoptosis. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein. [provided by RefSeq, Jul 2008]

TNFRSF10A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

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

BP6

Variant 8-23200675-T-C is Benign according to our data. Variant chr8-23200675-T-C is described in ClinVar as Benign. ClinVar VariationId is 1241396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF10A	NM_003844.4 link	c.703+12A>G		intron_variant	Intron 5 of 9	ENST00000221132.8	NP_003835.3	O00220

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNFRSF10A	ENST00000221132.8 link	c.703+12A>G	intron_variant	Intron 5 of 9	1	NM_003844.4	ENSP00000221132.3	O00220
TNFRSF10A	ENST00000613472.1 link	c.229+12A>G	intron_variant	Intron 4 of 8	1		ENSP00000480778.1	F8U8C0
TNFRSF10A	ENST00000524158.5 link	c.97+12A>G	intron_variant	Intron 5 of 6	5		ENSP00000428884.1	E5RFH1

Frequencies

GnomAD3 genomes

AF:

0.304

AC:

45988

AN:

151416

Hom.:

7281

Cov.:

show subpopulations

Gnomad AFR

AF:

0.321

Gnomad AMI

AF:

0.255

Gnomad AMR

AF:

0.346

Gnomad ASJ

AF:

0.242

Gnomad EAS

AF:

0.0580

Gnomad SAS

AF:

0.229

Gnomad FIN

AF:

0.345

Gnomad MID

AF:

0.264

Gnomad NFE

AF:

0.306

Gnomad OTH

AF:

0.284

GnomAD2 exomes

AF:

0.291

AC:

73073

AN:

251406

AF XY:

0.286

show subpopulations

Gnomad AFR exome

AF:

0.316

Gnomad AMR exome

AF:

0.384

Gnomad ASJ exome

AF:

0.236

Gnomad EAS exome

AF:

0.0516

Gnomad FIN exome

AF:

0.348

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.293

GnomAD4 exome

AF:

0.294

AC:

428147

AN:

1458208

Hom.:

64582

Cov.:

AF XY:

0.292

AC XY:

211924

AN XY:

725456

show subpopulations

African (AFR)

AF:

0.326

AC:

10855

AN:

33260

American (AMR)

AF:

0.383

AC:

17109

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

6146

AN:

25958

East Asian (EAS)

AF:

0.0749

AC:

2944

AN:

39326

South Asian (SAS)

AF:

0.252

AC:

21747

AN:

86222

European-Finnish (FIN)

AF:

0.351

AC:

18684

AN:

53188

Middle Eastern (MID)

AF:

0.280

AC:

1607

AN:

5748

European-Non Finnish (NFE)

AF:

0.299

AC:

332079

AN:

1109714

Other (OTH)

AF:

0.282

AC:

16976

AN:

60148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

16201

32401

48602

64802

81003

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10770

21540

32310

43080

53850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.304

AC:

45996

AN:

151536

Hom.:

7284

Cov.:

AF XY:

0.302

AC XY:

22350

AN XY:

74030

show subpopulations

African (AFR)

AF:

0.320

AC:

13238

AN:

41330

American (AMR)

AF:

0.346

AC:

5284

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.242

AC:

839

AN:

3468

East Asian (EAS)

AF:

0.0583

AC:

298

AN:

5114

South Asian (SAS)

AF:

0.228

AC:

1082

AN:

4750

European-Finnish (FIN)

AF:

0.345

AC:

3618

AN:

10474

Middle Eastern (MID)

AF:

0.243

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.306

AC:

20745

AN:

67824

Other (OTH)

AF:

0.280

AC:

589

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1585

3171

4756

6342

7927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

446

892

1338

1784

2230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.296

Hom.:

17635

Bravo

AF:

0.302

Asia WGS

AF:

0.152

AC:

534

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 18, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

2.1

(source)

DANN

Benign

0.37

PhyloP100

0.029

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over