chr12-6333835-G-A

Variant names:

• chr12-6333835-G-A
• rs4149637
• NM_001065.4:c.224C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001346091.2(TNFRSF1A):​c.-101C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00467 in 1,599,400 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.023 (139 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (133 hom.)
• Consequence: TNFRSF1A NM_001346091.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.72
• Publications: 33 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00295794).
• BP6: Variant 12-6333835-G-A is Benign according to our data. Variant chr12-6333835-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 245671.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0761 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346091.2. 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.224C>T	p.Pro75Leu	missense	Exon 3 of 10	NP_001056.1	P19438-1
	TNFRSF1A	NM_001346091.2		c.-101C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001333020.1	P19438-2
	TNFRSF1A	NM_001346092.2		c.-354C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 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.224C>T	p.Pro75Leu	missense	Exon 3 of 10	ENSP00000162749.2	P19438-1
	TNFRSF1A	ENST00000540022.5	TSL:1	c.193+256C>T		intron	N/A	ENSP00000438343.1	F5H061
	TNFRSF1A	ENST00000366159.9	TSL:1	n.258C>T		non_coding_transcript_exon	Exon 3 of 10

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3500 AN: 152142 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0782

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.00574 AC: 1290 AN: 224860 AF XY: 0.00421

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000399

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00274 AC: 3962 AN: 1447140 Hom.: 133 Cov.: 33 AF XY: 0.00241 AC XY: 1735 AN XY: 718564

African (AFR) AF: 0.0861 AC: 2861 AN: 33232

American (AMR) AF: 0.00546 AC: 231 AN: 42292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 39110

South Asian (SAS) AF: 0.000178 AC: 15 AN: 84270

European-Finnish (FIN) AF: 0.0000191 AC: 1 AN: 52396

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5752

European-Non Finnish (NFE) AF: 0.000414 AC: 457 AN: 1104444

Other (OTH) AF: 0.00626 AC: 375 AN: 59896

GnomAD4 genome AF: 0.0231 AC: 3513 AN: 152260 Hom.: 139 Cov.: 32 AF XY: 0.0214 AC XY: 1596 AN XY: 74432

African (AFR) AF: 0.0783 AC: 3255 AN: 41556

American (AMR) AF: 0.0125 AC: 192 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68020

Other (OTH) AF: 0.0171 AC: 36 AN: 2110

Alfa AF: 0.00787 Hom.: 104

Bravo AF: 0.0272

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0738 AC: 325

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00656 AC: 796

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	TNF receptor-associated periodic fever syndrome (TRAPS) (3)
-	1	-	Autoinflammatory syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.7
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.47
MVP		0.89
MPC		0.79
ClinPred		0.063	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.96
Mutation Taster		=94/6	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: rs4149637; hg19: chr12-6443001;