chr8-23224977-C-T

Variant names:

• chr8-23224977-C-T
• rs758645078
• NM_003844.4:c.85G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003844.4(TNFRSF10A):​c.85G>A​(p.Ala29Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000438 in 1,599,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TNFRSF10A NM_003844.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.944
• Publications: 0 publications found

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-DT (HGNC:52647): (TNFRSF10A divergent transcript)

ENSG00000250714 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09774253).
• BS2: High AC in GnomAdExome4 at 6 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.85G>A	p.Ala29Thr	missense	Exon 1 of 10	NP_003835.3
	TNFRSF10A-DT	NR_033928.1		n.-244C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF10A	ENST00000221132.8	TSL:1 MANE Select	c.85G>A	p.Ala29Thr	missense	Exon 1 of 10	ENSP00000221132.3	O00220
	TNFRSF10A	ENST00000613472.1	TSL:1	c.31+54G>A		intron	N/A	ENSP00000480778.1	F8U8C0
	TNFRSF10A	ENST00000901503.1		c.85G>A	p.Ala29Thr	missense	Exon 1 of 9	ENSP00000571562.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000879 AC: 2 AN: 227506 AF XY: 0.0000161

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000584

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000990

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1447528 Hom.: 0 Cov.: 31 AF XY: 0.00000417 AC XY: 3 AN XY: 718738

African (AFR) AF: 0.00 AC: 0 AN: 33136

American (AMR) AF: 0.00 AC: 0 AN: 43408

Ashkenazi Jewish (ASJ) AF: 0.0000388 AC: 1 AN: 25770

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39158

South Asian (SAS) AF: 0.00 AC: 0 AN: 84352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1104734

Other (OTH) AF: 0.0000335 AC: 2 AN: 59678

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.94
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.92	P
Vest4		0.15
MutPred		0.18		Loss of helix (P = 0.0093)
MVP		0.54
MPC		0.063
ClinPred		0.11	T
GERP RS		0.69
PromoterAI		-0.00060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.098
gMVP		0.12
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs758645078; hg19: chr8-23082490;