chr12-6332835-T-C

Variant names:

• chr12-6332835-T-C
• rs4149639
• NM_001065.4:c.551+234A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001065.4(TNFRSF1A):​c.551+234A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0601 in 152,256 control chromosomes in the GnomAD database, including 596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.060 (596 hom., cov: 31)
• Consequence: TNFRSF1A NM_001065.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.176
• Publications: 12 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine, Illumina

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-6332835-T-C is Benign according to our data. Variant chr12-6332835-T-C is described in ClinVar as Benign. ClinVar VariationId is 677250.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1A	NM_001065.4	c.551+234A>G		intron_variant	Intron 5 of 9	ENST00000162749.7	NP_001056.1
TNFRSF1A	NM_001346091.2	c.227+234A>G		intron_variant	Intron 4 of 8		NP_001333020.1
TNFRSF1A	NM_001346092.2	c.-27+234A>G		intron_variant	Intron 5 of 10		NP_001333021.1
TNFRSF1A	NR_144351.2	n.813+234A>G		intron_variant	Intron 5 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.551+234A>G		intron_variant	Intron 5 of 9	1	NM_001065.4	ENSP00000162749.2

Frequencies

GnomAD3 genomes AF: 0.0601 AC: 9138 AN: 152138 Hom.: 598 Cov.: 31

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0802

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.0794

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00770

Gnomad OTH AF: 0.0569

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0601 AC: 9158 AN: 152256 Hom.: 596 Cov.: 31 AF XY: 0.0617 AC XY: 4596 AN XY: 74466

African (AFR) AF: 0.157 AC: 6525 AN: 41524

American (AMR) AF: 0.0801 AC: 1226 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3470

East Asian (EAS) AF: 0.0796 AC: 412 AN: 5178

South Asian (SAS) AF: 0.0379 AC: 183 AN: 4828

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00767 AC: 522 AN: 68016

Other (OTH) AF: 0.0577 AC: 122 AN: 2114

Alfa AF: 0.0290 Hom.: 302

Bravo AF: 0.0682

Asia WGS AF: 0.0790 AC: 272 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.44
PhyloP100		0.18
Mutation Taster		=100/0	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: rs4149639; hg19: chr12-6442001;