chr1-12193005-G-A

Position:

• chr1-12193005-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000376259.7(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. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.025 (55 hom., cov: 33)
  • Exomes 𝑓: 0.034 (945 hom.)
• Consequence: TNFRSF1B ENST00000376259.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.29

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

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 55 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF1B	NM_001066.3	c.694G>A	p.Glu232Lys	missense_variant	6/10	ENST00000376259.7	NP_001057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1B	ENST00000376259.7	c.694G>A	p.Glu232Lys	missense_variant	6/10	1	NM_001066.3	ENSP00000365435	P1
TNFRSF1B	ENST00000492361.1	n.683G>A		non_coding_transcript_exon_variant	5/9	1
TNFRSF1B	ENST00000489921.1	n.406G>A		non_coding_transcript_exon_variant	3/3	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

GnomAD3 exomes AF: 0.0272 AC: 6840 AN: 251286 Hom.: 107 AF XY: 0.0276 AC XY: 3754 AN XY: 135834

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 SAS exome AF: 0.0231

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

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.00939

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.0408

Gnomad4 SAS exome AF: 0.0233

Gnomad4 FIN exome AF: 0.0228

Gnomad4 NFE exome AF: 0.0377

Gnomad4 OTH exome AF: 0.0311

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

Gnomad4 AFR AF: 0.0132

Gnomad4 AMR AF: 0.0129

Gnomad4 ASJ AF: 0.0253

Gnomad4 EAS AF: 0.0394

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.0241

Gnomad4 NFE AF: 0.0351

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0313 Hom.: 183

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 v4.3

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
MutationTaster	Benign	1.0	N
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

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