rs200029309

chr12-6329847-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001065.4(TNFRSF1A):c.988G>A(p.Ala330Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00043 in 1,601,444 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (1 hom.)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.43

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012302369).
• BP6: Variant 12-6329847-C-T is Benign according to our data. Variant chr12-6329847-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 378736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 43 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF1A	NM_001065.4	c.988G>A	p.Ala330Thr	missense_variant	9/10	ENST00000162749.7
TNFRSF1A	NM_001346091.2	c.664G>A	p.Ala222Thr	missense_variant	8/9
TNFRSF1A	NM_001346092.2	c.529G>A	p.Ala177Thr	missense_variant	10/11
TNFRSF1A	NR_144351.2	n.1176G>A		non_coding_transcript_exon_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.988G>A	p.Ala330Thr	missense_variant	9/10	1	NM_001065.4	P1

Frequencies

GnomAD3 genomes AF: 0.000283 AC: 43 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000279 AC: 63 AN: 225546 Hom.: 1 AF XY: 0.000302 AC XY: 37 AN XY: 122410

Gnomad AFR exome AF: 0.000285

Gnomad AMR exome AF: 0.0000632

Gnomad ASJ exome AF: 0.000625

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000537

Gnomad NFE exome AF: 0.000466

Gnomad OTH exome AF: 0.000535

GnomAD4 exome AF: 0.000445 AC: 645 AN: 1449198 Hom.: 1 Cov.: 32 AF XY: 0.000417 AC XY: 300 AN XY: 719946

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000141

Gnomad4 ASJ exome AF: 0.000425

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000765

Gnomad4 NFE exome AF: 0.000529

Gnomad4 OTH exome AF: 0.000569

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74434

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000517 Hom.: 1

Bravo AF: 0.000366

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000322 AC: 39

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2021	This variant is associated with the following publications: (PMID: 28746777) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	TNFRSF1A: BP4, BS2 -

TNF receptor-associated periodic fever syndrome (TRAPS) Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

- -

Autoinflammatory syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.14
Dann	Benign	0.78
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.0	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.099
Sift	Benign	0.80	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.026	B;B
Vest4		0.051
MVP		0.55
MPC		0.56
ClinPred		0.0073	T
GERP RS		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200029309; hg19: chr12-6439013;