8-23068839-C-T

Position:

• chr8-23068839-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003842.5(TNFRSF10B):​c.56G>A​(p.Gly19Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,262 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (18 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (20 hom.)
• Consequence: TNFRSF10B NM_003842.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0250

Genes affected

TNFRSF10B (HGNC:11905): (TNF receptor superfamily member 10b) The protein encoded by this gene is a member of the TNF-receptor superfamily, and contains an intracellular death domain. This receptor can be activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL/APO-2L), and transduces an apoptosis signal. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein. Two transcript variants encoding different isoforms and one non-coding transcript have been found for this gene. [provided by RefSeq, Mar 2009]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004155576).
• BP6: Variant 8-23068839-C-T is Benign according to our data. Variant chr8-23068839-C-T is described in ClinVar as [Benign]. Clinvar id is 714378.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00693 (1056/152328) while in subpopulation AFR AF= 0.0246 (1023/41576). AF 95% confidence interval is 0.0234. There are 18 homozygotes in gnomad4. There are 509 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1056 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF10B	NM_003842.5	c.56G>A	p.Gly19Asp	missense_variant	1/9	ENST00000276431.9	NP_003833.4
LOC286059	NR_038873.1	n.192+419C>T		intron_variant, non_coding_transcript_variant
TNFRSF10B	NM_147187.3	c.56G>A	p.Gly19Asp	missense_variant	1/10		NP_671716.2
TNFRSF10B	NR_027140.2	n.193G>A		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF10B	ENST00000276431.9	c.56G>A	p.Gly19Asp	missense_variant	1/9	1	NM_003842.5	ENSP00000276431	P2
	ENST00000501897.1	n.192+419C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00689 AC: 1049 AN: 152210 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00176 AC: 433 AN: 245908 Hom.: 6 AF XY: 0.00132 AC XY: 177 AN XY: 134366

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.000756

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000362

Gnomad OTH exome AF: 0.000333

GnomAD4 exome AF: 0.000754 AC: 1102 AN: 1460934 Hom.: 20 Cov.: 35 AF XY: 0.000603 AC XY: 438 AN XY: 726770

Gnomad4 AFR exome AF: 0.0284

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00693 AC: 1056 AN: 152328 Hom.: 18 Cov.: 33 AF XY: 0.00683 AC XY: 509 AN XY: 74488

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00300 Hom.: 3

Bravo AF: 0.00777

ESP6500AA AF: 0.0265 AC: 116

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00224 AC: 272

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.061	T;.
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.28	T;T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.20
Sift	Benign	0.30	T;T
Sift4G	Benign	0.085	T;T
Polyphen		0.90	P;P
Vest4		0.14
MVP		0.82
MPC		0.090
ClinPred		0.0024	T
GERP RS		-1.3
Varity_R		0.033
gMVP		0.36

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: rs41308114; hg19: chr8-22926352; COSMIC: COSV99035323; COSMIC: COSV99035323;