8-23137998-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003840.5(TNFRSF10D):c.1033A>C(p.Thr345Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00446 in 1,614,080 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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.

• Frequency:
  • Genomes: 𝑓 0.024 (155 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (119 hom.)
• Consequence: TNFRSF10D NM_003840.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.312

Genes affected

TNFRSF10D (HGNC:11907): (TNF receptor superfamily member 10d) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor contains an extracellular TRAIL-binding domain, a transmembrane domain, and a truncated cytoplamic death domain. This receptor does not induce apoptosis, and has been shown to play an inhibitory role in TRAIL-induced cell apoptosis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020661056).
• BP6: Variant 8-23137998-T-G is Benign according to our data. Variant chr8-23137998-T-G is described in ClinVar as [Benign]. Clinvar id is 776293.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0814 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF10D	NM_003840.5	c.1033A>C	p.Thr345Pro	missense_variant	9/9	ENST00000312584.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF10D	ENST00000312584.4	c.1033A>C	p.Thr345Pro	missense_variant	9/9	1	NM_003840.5	P1

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3662 AN: 152146 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.0839

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00636 AC: 1599 AN: 251284 Hom.: 59 AF XY: 0.00471 AC XY: 640 AN XY: 135806

Gnomad AFR exome AF: 0.0884

Gnomad AMR exome AF: 0.00341

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: 0.000211

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00242 AC: 3531 AN: 1461816 Hom.: 119 Cov.: 31 AF XY: 0.00208 AC XY: 1513 AN XY: 727214

Gnomad4 AFR exome AF: 0.0837

Gnomad4 AMR exome AF: 0.00389

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000173

Gnomad4 OTH exome AF: 0.00558

GnomAD4 genome AF: 0.0241 AC: 3665 AN: 152264 Hom.: 155 Cov.: 32 AF XY: 0.0233 AC XY: 1738 AN XY: 74460

Gnomad4 AFR AF: 0.0837

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0109 Hom.: 50

Bravo AF: 0.0282

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0831 AC: 366

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00764 AC: 927

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 19, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	5.0
Dann	Benign	0.49
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.039	N
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Benign	0.19	T
Sift4G	Benign	0.075	T
Vest4		0.19
MVP		0.59
MPC		0.18
ClinPred		0.0029	T
GERP RS		1.9
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs34622674; hg19: chr8-22995511;