rs4149639

chr12-6332835-T-C

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
TNFRSF1A	NM_001065.4	c.551+234A>G		intron_variant		ENST00000162749.7
TNFRSF1A	NM_001346091.2	c.227+234A>G		intron_variant
TNFRSF1A	NM_001346092.2	c.-27+234A>G		intron_variant
TNFRSF1A	NR_144351.2	n.813+234A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.551+234A>G		intron_variant		1	NM_001065.4	P1

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

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.0801

Gnomad4 ASJ AF: 0.0346

Gnomad4 EAS AF: 0.0796

Gnomad4 SAS AF: 0.0379

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.00767

Gnomad4 OTH AF: 0.0577

Alfa AF: 0.0206 Hom.: 128

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs4149639; hg19: chr12-6442001;