8-23199391-T-G

Position:

• chr8-23199391-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000221132.8(TNFRSF10A):​c.889A>C​(p.Asn297His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,614,144 control chromosomes in the GnomAD database, including 121 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. N297N) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.016 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (60 hom.)
• Consequence: TNFRSF10A ENST00000221132.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.20

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031134188).
• BP6: Variant 8-23199391-T-G is Benign according to our data. Variant chr8-23199391-T-G is described in ClinVar as [Benign]. Clinvar id is 729941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF10A	NM_003844.4	c.889A>C	p.Asn297His	missense_variant	8/10	ENST00000221132.8	NP_003835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF10A	ENST00000221132.8	c.889A>C	p.Asn297His	missense_variant	8/10	1	NM_003844.4	ENSP00000221132	P1
TNFRSF10A	ENST00000613472.1	c.415A>C	p.Asn139His	missense_variant	7/9	1		ENSP00000480778

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2388 AN: 152176 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0549

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00374 AC: 940 AN: 251410 Hom.: 24 AF XY: 0.00270 AC XY: 367 AN XY: 135890

Gnomad AFR exome AF: 0.0525

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00152 AC: 2225 AN: 1461850 Hom.: 60 Cov.: 31 AF XY: 0.00127 AC XY: 927 AN XY: 727226

Gnomad4 AFR exome AF: 0.0561

Gnomad4 AMR exome AF: 0.00241

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00343

GnomAD4 genome AF: 0.0157 AC: 2390 AN: 152294 Hom.: 61 Cov.: 32 AF XY: 0.0153 AC XY: 1140 AN XY: 74468

Gnomad4 AFR AF: 0.0548

Gnomad4 AMR AF: 0.00536

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00334 Hom.: 17

Bravo AF: 0.0181

ESP6500AA AF: 0.0495 AC: 218

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00470 AC: 571

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 15, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.059	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0031	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Benign	0.25
Sift	Benign	0.032	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.26
MVP		0.72
MPC		0.37
ClinPred		0.037	T
GERP RS		2.6
Varity_R		0.28
gMVP		0.37

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: rs17088980; hg19: chr8-23056904;