NM_001066.3:c.694G>A

Variant names:

• chr1-12193005-G-A
• rs5746026
• NM_001066.3:c.694G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001066.3(TNFRSF1B):​c.694G>A​(p.Glu232Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0335 in 1,614,192 control chromosomes in the GnomAD database, including 1,000 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.025 (55 hom., cov: 33)
  • Exomes 𝑓: 0.034 (945 hom.)
• Consequence: TNFRSF1B NM_001066.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29
• Publications: 29 publications found

Genes affected

TNFRSF1B (HGNC:11917): (TNF receptor superfamily member 1B) The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein and TNF-receptor 1 form a heterocomplex that mediates the recruitment of two anti-apoptotic proteins, c-IAP1 and c-IAP2, which possess E3 ubiquitin ligase activity. The function of IAPs in TNF-receptor signalling is unknown, however, c-IAP1 is thought to potentiate TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2, which mediates anti-apoptotic signals. Knockout studies in mice also suggest a role of this protein in protecting neurons from apoptosis by stimulating antioxidative pathways. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024419427).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0255 (3883/152324) while in subpopulation EAS AF = 0.0394 (204/5182). AF 95% confidence interval is 0.0349. There are 55 homozygotes in GnomAd4. There are 1806 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 55 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001066.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1B	NM_001066.3	MANE Select	c.694G>A	p.Glu232Lys	missense	Exon 6 of 10	NP_001057.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1B	ENST00000376259.7	TSL:1 MANE Select	c.694G>A	p.Glu232Lys	missense	Exon 6 of 10	ENSP00000365435.3
	TNFRSF1B	ENST00000492361.1	TSL:1	n.683G>A		non_coding_transcript_exon	Exon 5 of 9
	TNFRSF1B	ENST00000489921.1	TSL:3	n.406G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0255 AC: 3885 AN: 152204 Hom.: 55 Cov.: 33

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.0395

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0352

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0272 AC: 6840 AN: 251286 AF XY: 0.0276

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.00850

Gnomad ASJ exome AF: 0.0247

Gnomad EAS exome AF: 0.0373

Gnomad FIN exome AF: 0.0216

Gnomad NFE exome AF: 0.0357

Gnomad OTH exome AF: 0.0240

GnomAD4 exome AF: 0.0343 AC: 50142 AN: 1461868 Hom.: 945 Cov.: 34 AF XY: 0.0338 AC XY: 24608 AN XY: 727236

African (AFR) AF: 0.0122 AC: 409 AN: 33480

American (AMR) AF: 0.00939 AC: 420 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 660 AN: 26136

East Asian (EAS) AF: 0.0408 AC: 1621 AN: 39700

South Asian (SAS) AF: 0.0233 AC: 2008 AN: 86252

European-Finnish (FIN) AF: 0.0228 AC: 1216 AN: 53420

Middle Eastern (MID) AF: 0.00936 AC: 54 AN: 5768

European-Non Finnish (NFE) AF: 0.0377 AC: 41873 AN: 1111994

Other (OTH) AF: 0.0311 AC: 1881 AN: 60396

GnomAD4 genome AF: 0.0255 AC: 3883 AN: 152324 Hom.: 55 Cov.: 33 AF XY: 0.0243 AC XY: 1806 AN XY: 74472

African (AFR) AF: 0.0132 AC: 549 AN: 41570

American (AMR) AF: 0.0129 AC: 198 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 88 AN: 3472

East Asian (EAS) AF: 0.0394 AC: 204 AN: 5182

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4826

European-Finnish (FIN) AF: 0.0241 AC: 256 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0351 AC: 2391 AN: 68028

Other (OTH) AF: 0.0218 AC: 46 AN: 2112

Alfa AF: 0.0315 Hom.: 351

Bravo AF: 0.0239

TwinsUK AF: 0.0415 AC: 154

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.0344 AC: 296

ExAC AF: 0.0287 AC: 3482

Asia WGS AF: 0.0330 AC: 116 AN: 3478

EpiCase AF: 0.0325

EpiControl AF: 0.0302

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.11
Sift	Benign	0.70	T
Sift4G	Uncertain	0.039	D
Polyphen		0.042	B
Vest4		0.041
MPC		0.40
ClinPred		0.0039	T
GERP RS		2.2
Varity_R		0.029
gMVP		0.55
Mutation Taster		=98/2	polymorphism (auto)

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: rs5746026; hg19: chr1-12253062; COSMIC: COSV66163938; COSMIC: COSV66163938;