Genetic Variant NM_003844.4:c.1322G>A (chr8-23191779-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_003844.4(TNFRSF10A):c.1322G>A(p.Arg441Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.86 in 1,614,030 control chromosomes in the GnomAD database, including 598,025 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.86 ( 56528 hom., cov: 31)

Exomes 𝑓: 0.86 ( 541497 hom. )

Consequence

TNFRSF10A
NM_003844.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0950

Publications

60 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.6099135E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.957 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF10A	NM_003844.4 link	c.1322G>A	p.Arg441Lys	missense_variant	Exon 10 of 10	ENST00000221132.8	NP_003835.3	O00220

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNFRSF10A	ENST00000221132.8 link	c.1322G>A	p.Arg441Lys	missense_variant	Exon 10 of 10	1	NM_003844.4	ENSP00000221132.3	O00220
TNFRSF10A	ENST00000613472.1 link	c.848G>A	p.Arg283Lys	missense_variant	Exon 9 of 9	1		ENSP00000480778.1	F8U8C0
TNFRSF10A	ENST00000519862.1 link	n.*35G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.861

AC:

130891

AN:

152030

Hom.:

56471

Cov.:

show subpopulations

Gnomad AFR

AF:

0.865

Gnomad AMI

AF:

0.726

Gnomad AMR

AF:

0.904

Gnomad ASJ

AF:

0.889

Gnomad EAS

AF:

0.979

Gnomad SAS

AF:

0.954

Gnomad FIN

AF:

0.792

Gnomad MID

AF:

0.861

Gnomad NFE

AF:

0.844

Gnomad OTH

AF:

0.872

GnomAD2 exomes

AF:

0.880

AC:

221372

AN:

251456

AF XY:

0.882

show subpopulations

Gnomad AFR exome

AF:

0.862

Gnomad AMR exome

AF:

0.937

Gnomad ASJ exome

AF:

0.891

Gnomad EAS exome

AF:

0.981

Gnomad FIN exome

AF:

0.800

Gnomad NFE exome

AF:

0.845

Gnomad OTH exome

AF:

0.876

GnomAD4 exome

AF:

0.860

AC:

1257001

AN:

1461882

Hom.:

541497

Cov.:

AF XY:

0.863

AC XY:

627266

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.867

AC:

29033

AN:

33480

American (AMR)

AF:

0.932

AC:

41698

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.895

AC:

23386

AN:

26136

East Asian (EAS)

AF:

0.986

AC:

39153

AN:

39700

South Asian (SAS)

AF:

0.951

AC:

82008

AN:

86258

European-Finnish (FIN)

AF:

0.804

AC:

42929

AN:

53410

Middle Eastern (MID)

AF:

0.888

AC:

5121

AN:

5768

European-Non Finnish (NFE)

AF:

0.846

AC:

941138

AN:

1112010

Other (OTH)

AF:

0.870

AC:

52535

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

11709

23417

35126

46834

58543

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21202

42404

63606

84808

106010

<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:

0.861

AC:

131004

AN:

152148

Hom.:

56528

Cov.:

AF XY:

0.861

AC XY:

64034

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.866

AC:

35942

AN:

41522

American (AMR)

AF:

0.904

AC:

13823

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.889

AC:

3082

AN:

3468

East Asian (EAS)

AF:

0.979

AC:

5070

AN:

5178

South Asian (SAS)

AF:

0.954

AC:

4597

AN:

4818

European-Finnish (FIN)

AF:

0.792

AC:

8373

AN:

10576

Middle Eastern (MID)

AF:

0.844

AC:

248

AN:

294

European-Non Finnish (NFE)

AF:

0.844

AC:

57363

AN:

67980

Other (OTH)

AF:

0.874

AC:

1847

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

904

1808

2711

3615

4519

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

898

1796

2694

3592

4490

<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:

0.855

Hom.:

263958

Bravo

AF:

0.867

TwinsUK

AF:

0.847

AC:

3142

ALSPAC

AF:

0.844

AC:

3254

ESP6500AA

AF:

0.856

AC:

3773

ESP6500EA

AF:

0.846

AC:

7273

ExAC

AF:

0.878

AC:

106618

Asia WGS

AF:

0.959

AC:

3333

AN:

3478

EpiCase

AF:

0.849

EpiControl

AF:

0.847

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.049

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.064

T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.16

T;T

MetaRNN

Benign

8.6e-7

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.3

N;.

PhyloP100

-0.095

PrimateAI

Benign

0.28

PROVEAN

Benign

1.4

N;.

REVEL

Benign

0.20

Sift

Benign

1.0

T;.

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;.

Vest4

0.047

MPC

0.065

ClinPred

0.00023

GERP RS

-2.6

Varity_R

0.035

gMVP

0.41

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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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