Genetic Variant TNFRSF10A:p.Ter469Leuext*? (chr8-23191695-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM4BP6_ModerateBS2

The NM_003844.4(TNFRSF10A):c.1406G>T(p.Ter469Leuext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000875 in 1,610,852 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00088 ( 3 hom. )

Consequence

TNFRSF10A
NM_003844.4 stop_lost

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.240

Publications

5 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: Likely_benign. The variant received -4 ACMG points.

PM4

Stoplost variant in NM_003844.4 Downstream stopcodon found after 23 codons.

BP6

Variant 8-23191695-C-A is Benign according to our data. Variant chr8-23191695-C-A is described in ClinVar as Benign. ClinVar VariationId is 784502.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 121 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003844.4. 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
	TNFRSF10A	NM_003844.4	MANE Select	c.1406G>T	p.Ter469Leuext*?	stop_lost	Exon 10 of 10	NP_003835.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF10A	ENST00000221132.8	TSL:1 MANE Select	c.1406G>T	p.Ter469Leuext*?	stop_lost	Exon 10 of 10	ENSP00000221132.3	O00220
TNFRSF10A	ENST00000613472.1	TSL:1	c.932G>T	p.Ter311Leuext*?	stop_lost	Exon 9 of 9	ENSP00000480778.1	F8U8C0
TNFRSF10A	ENST00000901503.1		c.1310G>T	p.Ter437Leuext*?	stop_lost	Exon 9 of 9	ENSP00000571562.1

Frequencies

GnomAD3 genomes

AF:

0.000796

AC:

121

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00131

AC:

325

AN:

247736

AF XY:

0.00131

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.00134

Gnomad ASJ exome

AF:

0.0148

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000937

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00216

GnomAD4 exome

AF:

0.000883

AC:

1288

AN:

1458698

Hom.:

Cov.:

AF XY:

0.000912

AC XY:

662

AN XY:

725526

show subpopulations

African (AFR)

AF:

0.0000902

AC:

AN:

33264

American (AMR)

AF:

0.00135

AC:

AN:

44310

Ashkenazi Jewish (ASJ)

AF:

0.0144

AC:

373

AN:

25900

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.0000233

AC:

AN:

86008

European-Finnish (FIN)

AF:

0.0000564

AC:

AN:

53172

Middle Eastern (MID)

AF:

0.00209

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.000652

AC:

724

AN:

1110414

Other (OTH)

AF:

0.00184

AC:

111

AN:

60224

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

138

207

276

345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.000795

AC:

121

AN:

152154

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41522

American (AMR)

AF:

0.000523

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00146

Hom.:

Bravo

AF:

0.000960

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00119

AC:

145

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00202

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.41

(source)

DANN

Benign

0.72

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.60

FATHMM_MKL

Benign

0.018

PhyloP100

-0.24

Vest4

0.16

GERP RS

-1.7

Mutation Taster

=198/2

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over