rs1800693

Variant names:

• chr12-6330843-T-C
• rs1800693
• NM_001065.4:c.625+10A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-6330843-T-C
• chr12-6330843-T-A
• chr12-6330843-T-G

Variant summary

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

The NM_001065.4(TNFRSF1A):​c.625+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 1,611,606 control chromosomes in the GnomAD database, including 123,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (10910 hom., cov: 30)
  • Exomes 𝑓: 0.39 (112398 hom.)
• Consequence: TNFRSF1A NM_001065.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:3 B:11 O:2
• Conservation: PhyloP100: 0.172
• Publications: 218 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-6330843-T-C is Benign according to our data. Variant chr12-6330843-T-C is described in ClinVar as Benign. ClinVar VariationId is 37038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

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.625+10A>G		intron	N/A	NP_001056.1	P19438-1
	TNFRSF1A	NM_001346091.2		c.301+10A>G		intron	N/A	NP_001333020.1	P19438-2
	TNFRSF1A	NM_001346092.2		c.166+10A>G		intron	N/A	NP_001333021.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1A	ENST00000162749.7	TSL:1 MANE Select	c.625+10A>G		intron	N/A	ENSP00000162749.2	P19438-1
	TNFRSF1A	ENST00000540022.5	TSL:1	c.496+10A>G		intron	N/A	ENSP00000438343.1	F5H061
	TNFRSF1A	ENST00000366159.9	TSL:1	n.1726+10A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56939 AN: 151700 Hom.: 10912 Cov.: 30

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.374

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.413

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.361

GnomAD2 exomes AF: 0.361 AC: 90633 AN: 251114 AF XY: 0.361

Gnomad AFR exome AF: 0.347

Gnomad AMR exome AF: 0.332

Gnomad ASJ exome AF: 0.402

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.408

Gnomad OTH exome AF: 0.379

GnomAD4 exome AF: 0.388 AC: 566393 AN: 1459786 Hom.: 112398 Cov.: 33 AF XY: 0.387 AC XY: 281181 AN XY: 726316

African (AFR) AF: 0.350 AC: 11710 AN: 33448

American (AMR) AF: 0.327 AC: 14638 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.401 AC: 10481 AN: 26120

East Asian (EAS) AF: 0.159 AC: 6314 AN: 39692

South Asian (SAS) AF: 0.313 AC: 26987 AN: 86208

European-Finnish (FIN) AF: 0.412 AC: 21969 AN: 53382

Middle Eastern (MID) AF: 0.389 AC: 2175 AN: 5594

European-Non Finnish (NFE) AF: 0.405 AC: 449664 AN: 1110320

Other (OTH) AF: 0.372 AC: 22455 AN: 60314

GnomAD4 genome AF: 0.375 AC: 56939 AN: 151820 Hom.: 10910 Cov.: 30 AF XY: 0.374 AC XY: 27718 AN XY: 74180

African (AFR) AF: 0.348 AC: 14385 AN: 41368

American (AMR) AF: 0.354 AC: 5390 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.413 AC: 1429 AN: 3464

East Asian (EAS) AF: 0.136 AC: 702 AN: 5168

South Asian (SAS) AF: 0.302 AC: 1451 AN: 4806

European-Finnish (FIN) AF: 0.414 AC: 4361 AN: 10524

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 28008 AN: 67938

Other (OTH) AF: 0.359 AC: 755 AN: 2104

Alfa AF: 0.394 Hom.: 52673

Bravo AF: 0.368

Asia WGS AF: 0.230 AC: 800 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (4)
-	-	2	TNF receptor-associated periodic fever syndrome (TRAPS) (2)
-	1	-	Associated with severe COVID-19 disease (1)
-	-	1	Autoinflammatory syndrome (1)
-	1	-	Susceptibility to severe coronavirus disease (COVID-19) (1)
-	1	-	Susceptibility to severe coronavirus disease (COVID-19) due to high plasma levels of TNF, TNFR, and/or TNFR6 (1)
-	-	-	Multiple sclerosis, susceptibility to, 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.73
PhyloP100		0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1800693; hg19: chr12-6440009; COSMIC: COSV50598984; COSMIC: COSV50598984;