NM_003844.4:c.683A>C

Variant names:

• chr8-23200707-T-G
• rs20576
• NM_003844.4:c.683A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003844.4(TNFRSF10A):​c.683A>C​(p.Glu228Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,605,418 control chromosomes in the GnomAD database, including 28,771 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1965 hom., cov: 31)
  • Exomes 𝑓: 0.19 (26806 hom.)
• Consequence: TNFRSF10A NM_003844.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.03
• Publications: 65 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010643601).
• BP6: Variant 8-23200707-T-G is Benign according to our data. Variant chr8-23200707-T-G is described in ClinVar as Benign. ClinVar VariationId is 1253334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

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.683A>C	p.Glu228Ala	missense	Exon 5 of 10	NP_003835.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF10A	ENST00000221132.8	TSL:1 MANE Select	c.683A>C	p.Glu228Ala	missense	Exon 5 of 10	ENSP00000221132.3	O00220
	TNFRSF10A	ENST00000613472.1	TSL:1	c.209A>C	p.Glu70Ala	missense	Exon 4 of 9	ENSP00000480778.1	F8U8C0
	TNFRSF10A	ENST00000901503.1		c.683A>C	p.Glu228Ala	missense	Exon 5 of 9	ENSP00000571562.1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21716 AN: 151290 Hom.: 1965 Cov.: 31

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0927

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.162

GnomAD2 exomes AF: 0.151 AC: 38009 AN: 251454 AF XY: 0.155

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.0159

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.185 AC: 269208 AN: 1454004 Hom.: 26806 Cov.: 53 AF XY: 0.183 AC XY: 132429 AN XY: 723542

African (AFR) AF: 0.0320 AC: 1055 AN: 32938

American (AMR) AF: 0.111 AC: 4949 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 5156 AN: 25846

East Asian (EAS) AF: 0.0148 AC: 578 AN: 38964

South Asian (SAS) AF: 0.0925 AC: 7973 AN: 86186

European-Finnish (FIN) AF: 0.216 AC: 11365 AN: 52542

Middle Eastern (MID) AF: 0.181 AC: 1037 AN: 5736

European-Non Finnish (NFE) AF: 0.205 AC: 226902 AN: 1107580

Other (OTH) AF: 0.171 AC: 10193 AN: 59758

GnomAD4 genome AF: 0.143 AC: 21712 AN: 151414 Hom.: 1965 Cov.: 31 AF XY: 0.144 AC XY: 10647 AN XY: 73964

African (AFR) AF: 0.0377 AC: 1559 AN: 41316

American (AMR) AF: 0.143 AC: 2174 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 707 AN: 3466

East Asian (EAS) AF: 0.0161 AC: 82 AN: 5108

South Asian (SAS) AF: 0.0933 AC: 445 AN: 4768

European-Finnish (FIN) AF: 0.231 AC: 2408 AN: 10434

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13710 AN: 67798

Other (OTH) AF: 0.160 AC: 336 AN: 2096

Alfa AF: 0.177 Hom.: 8638

Bravo AF: 0.134

TwinsUK AF: 0.206 AC: 764

ALSPAC AF: 0.195 AC: 753

ESP6500AA AF: 0.0470 AC: 207

ESP6500EA AF: 0.200 AC: 1720

ExAC AF: 0.149 AC: 18104

Asia WGS AF: 0.0600 AC: 208 AN: 3478

EpiCase AF: 0.210

EpiControl AF: 0.217

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.0
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.11
Sift	Benign	0.037	D
Sift4G	Uncertain	0.053	T
Polyphen		0.31	B
Vest4		0.13
MPC		0.12
ClinPred		0.0099	T
GERP RS		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.61
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs20576; hg19: chr8-23058220; COSMIC: COSV55325303; COSMIC: COSV55325303;