chr12-6341779-T-C

Variant names:

• chr12-6341779-T-C
• rs767455
• NM_001065.4:c.36A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001065.4(TNFRSF1A):​c.36A>G​(p.Pro12Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,612 control chromosomes in the GnomAD database, including 135,701 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12088 hom., cov: 33)
  • Exomes 𝑓: 0.41 (123613 hom.)
• Consequence: TNFRSF1A NM_001065.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:3 B:10 O:1
• Conservation: PhyloP100: -0.107
• Publications: 161 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 12-6341779-T-C is Benign according to our data. Variant chr12-6341779-T-C is described in ClinVar as Benign. ClinVar VariationId is 257326.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.107 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.432 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.36A>G	p.Pro12Pro	synonymous	Exon 1 of 10	NP_001056.1	P19438-1
	TNFRSF1A	NM_001346091.2		c.-135A>G		5_prime_UTR	Exon 1 of 9	NP_001333020.1	P19438-2
	TNFRSF1A	NM_001346092.2		c.-542A>G		5_prime_UTR	Exon 1 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.36A>G	p.Pro12Pro	synonymous	Exon 1 of 10	ENSP00000162749.2	P19438-1
	TNFRSF1A	ENST00000540022.5	TSL:1	c.36A>G	p.Pro12Pro	synonymous	Exon 1 of 9	ENSP00000438343.1	F5H061
	TNFRSF1A	ENST00000366159.9	TSL:1	n.70A>G		non_coding_transcript_exon	Exon 1 of 10

Frequencies

GnomAD3 genomes AF: 0.393 AC: 59765 AN: 152026 Hom.: 12096 Cov.: 33

Gnomad AFR AF: 0.357

Gnomad AMI AF: 0.438

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.382

GnomAD2 exomes AF: 0.374 AC: 93640 AN: 250294 AF XY: 0.374

Gnomad AFR exome AF: 0.356

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.141

Gnomad FIN exome AF: 0.457

Gnomad NFE exome AF: 0.429

Gnomad OTH exome AF: 0.398

GnomAD4 exome AF: 0.406 AC: 593442 AN: 1461468 Hom.: 123613 Cov.: 46 AF XY: 0.404 AC XY: 293957 AN XY: 727038

African (AFR) AF: 0.357 AC: 11934 AN: 33474

American (AMR) AF: 0.332 AC: 14830 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 10935 AN: 26124

East Asian (EAS) AF: 0.158 AC: 6257 AN: 39698

South Asian (SAS) AF: 0.297 AC: 25600 AN: 86244

European-Finnish (FIN) AF: 0.458 AC: 24416 AN: 53320

Middle Eastern (MID) AF: 0.409 AC: 2354 AN: 5760

European-Non Finnish (NFE) AF: 0.426 AC: 473415 AN: 1111736

Other (OTH) AF: 0.392 AC: 23701 AN: 60390

GnomAD4 genome AF: 0.393 AC: 59763 AN: 152144 Hom.: 12088 Cov.: 33 AF XY: 0.391 AC XY: 29083 AN XY: 74394

African (AFR) AF: 0.356 AC: 14785 AN: 41510

American (AMR) AF: 0.364 AC: 5567 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1475 AN: 3472

East Asian (EAS) AF: 0.135 AC: 698 AN: 5166

South Asian (SAS) AF: 0.287 AC: 1386 AN: 4830

European-Finnish (FIN) AF: 0.461 AC: 4881 AN: 10588

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.436 AC: 29647 AN: 67976

Other (OTH) AF: 0.380 AC: 804 AN: 2114

Alfa AF: 0.415 Hom.: 33815

Bravo AF: 0.383

Asia WGS AF: 0.225 AC: 784 AN: 3478

EpiCase AF: 0.439

EpiControl AF: 0.432

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	-	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 TNFR7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		-0.11
PromoterAI		-0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs767455; hg19: chr12-6450945; COSMIC: COSV50827987; COSMIC: COSV50827987;