12-6333477-C-T

Variant names:

• chr12-6333477-C-T
• rs4149584
• NM_001065.4:c.362G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 4P and 13B. PM1 PM5 BP4_Strong BP6 BS1 BS2

The NM_001065.4(TNFRSF1A):​c.362G>A​(p.Arg121Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0156 in 1,613,480 control chromosomes in the GnomAD database, including 235 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R121P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 32)
  • Exomes 𝑓: 0.016 (223 hom.)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8 B:10 O:1
• Conservation: PhyloP100: -1.46
• Publications: 134 publications found

Genes affected

TNFRSF1A (HGNC:11916): (TNF receptor superfamily member 1A) This gene encodes a member of the TNF receptor superfamily of proteins. The encoded receptor is found in membrane-bound and soluble forms that interact with membrane-bound and soluble forms, respectively, of its ligand, tumor necrosis factor alpha. Binding of membrane-bound tumor necrosis factor alpha to the membrane-bound receptor induces receptor trimerization and activation, which plays a role in cell survival, apoptosis, and inflammation. Proteolytic processing of the encoded receptor results in release of the soluble form of the receptor, which can interact with free tumor necrosis factor alpha to inhibit inflammation. Mutations in this gene underlie tumor necrosis factor receptor-associated periodic syndrome (TRAPS), characterized by fever, abdominal pain and other features. Mutations in this gene may also be associated with multiple sclerosis in human patients. [provided by RefSeq, Sep 2016]

TNFRSF1A Gene-Disease associations (from GenCC):

• TNF receptor 1-associated periodic fever syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Illumina, Laboratory for Molecular Medicine, Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001065.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-6333477-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 12341.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0070558786).
• BP6: Variant 12-6333477-C-T is Benign according to our data. Variant chr12-6333477-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 217017.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.012 (1824/151614) while in subpopulation NFE AF = 0.0192 (1302/67788). AF 95% confidence interval is 0.0183. There are 12 homozygotes in GnomAd4. There are 852 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1824 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001065.4. 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
	TNFRSF1A	NM_001065.4	MANE Select	c.362G>A	p.Arg121Gln	missense	Exon 4 of 10	NP_001056.1	P19438-1
	TNFRSF1A	NM_001346091.2		c.38G>A	p.Arg13Gln	missense	Exon 3 of 9	NP_001333020.1	P19438-2
	TNFRSF1A	NM_001346092.2		c.-216G>A		5_prime_UTR	Exon 4 of 11	NP_001333021.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1A	ENST00000162749.7	TSL:1 MANE Select	c.362G>A	p.Arg121Gln	missense	Exon 4 of 10	ENSP00000162749.2	P19438-1
	TNFRSF1A	ENST00000540022.5	TSL:1	c.233G>A	p.Arg78Gln	missense	Exon 3 of 9	ENSP00000438343.1	F5H061
	TNFRSF1A	ENST00000366159.9	TSL:1	n.396G>A		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1824 AN: 151496 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00337

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.0205

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00334

Gnomad FIN AF: 0.00851

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0132 AC: 3312 AN: 251342 AF XY: 0.0131

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00902

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0113

Gnomad NFE exome AF: 0.0203

Gnomad OTH exome AF: 0.0181

GnomAD4 exome AF: 0.0160 AC: 23389 AN: 1461866 Hom.: 223 Cov.: 33 AF XY: 0.0159 AC XY: 11529 AN XY: 727228

African (AFR) AF: 0.00254 AC: 85 AN: 33480

American (AMR) AF: 0.0105 AC: 471 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 484 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00398 AC: 343 AN: 86252

European-Finnish (FIN) AF: 0.0124 AC: 661 AN: 53416

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5768

European-Non Finnish (NFE) AF: 0.0183 AC: 20402 AN: 1111994

Other (OTH) AF: 0.0146 AC: 883 AN: 60396

GnomAD4 genome AF: 0.0120 AC: 1824 AN: 151614 Hom.: 12 Cov.: 32 AF XY: 0.0115 AC XY: 852 AN XY: 74078

African (AFR) AF: 0.00336 AC: 139 AN: 41326

American (AMR) AF: 0.0115 AC: 176 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 71 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00355 AC: 17 AN: 4786

European-Finnish (FIN) AF: 0.00851 AC: 90 AN: 10578

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0192 AC: 1302 AN: 67788

Other (OTH) AF: 0.0114 AC: 24 AN: 2102

Alfa AF: 0.0180 Hom.: 107

Bravo AF: 0.0121

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0186 AC: 160

ExAC AF: 0.0140 AC: 1703

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0196

EpiControl AF: 0.0203

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	3	4	TNF receptor-associated periodic fever syndrome (TRAPS) (9)
-	3	3	not provided (6)
-	-	3	not specified (3)
-	1	-	Autoinflammatory syndrome (1)
-	1	-	TNF receptor-associated periodic fever syndrome (TRAPS);C3553728:Multiple sclerosis, susceptibility to, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	2.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0071	T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.17	N
PhyloP100		-1.5
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.59	N
REVEL	Uncertain	0.56
Sift	Benign	0.48	T
Sift4G	Benign	0.26	T
Polyphen		0.68	P
Vest4		0.096
MPC		0.66
ClinPred		0.0054	T
GERP RS		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.91
Mutation Taster		=83/17	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4149584; hg19: chr12-6442643; COSMIC: COSV50610888; COSMIC: COSV50610888;