rs4149637

chr12-6333835-G-Achr12-6333835-G-Cchr12-6333835-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BA1

The NM_001065.4(TNFRSF1A):c.224C>T(p.Pro75Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00467 in 1,599,400 control chromosomes in the GnomAD database, including 272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P75P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (139 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (133 hom.)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.72

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 -11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_001065.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.00295794).
• BP6: Variant 12-6333835-G-A is Benign according to our data. Variant chr12-6333835-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 245671.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=2, Uncertain_significance=1}. Variant chr12-6333835-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF1A	NM_001065.4	c.224C>T	p.Pro75Leu	missense_variant	3/10	ENST00000162749.7
TNFRSF1A	NM_001346091.2	c.-101C>T		5_prime_UTR_variant	2/9
TNFRSF1A	NM_001346092.2	c.-354C>T		5_prime_UTR_variant	3/11
TNFRSF1A	NR_144351.2	n.486C>T		non_coding_transcript_exon_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.224C>T	p.Pro75Leu	missense_variant	3/10	1	NM_001065.4	P1

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3500 AN: 152142 Hom.: 138 Cov.: 32

Gnomad AFR AF: 0.0782

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00574 AC: 1290 AN: 224860 Hom.: 47 AF XY: 0.00421 AC XY: 510 AN XY: 121194

Gnomad AFR exome AF: 0.0800

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000399

Gnomad OTH exome AF: 0.00230

GnomAD4 exome AF: 0.00274 AC: 3962 AN: 1447140 Hom.: 133 Cov.: 33 AF XY: 0.00241 AC XY: 1735 AN XY: 718564

Gnomad4 AFR exome AF: 0.0861

Gnomad4 AMR exome AF: 0.00546

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000178

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000414

Gnomad4 OTH exome AF: 0.00626

GnomAD4 genome AF: 0.0231 AC: 3513 AN: 152260 Hom.: 139 Cov.: 32 AF XY: 0.0214 AC XY: 1596 AN XY: 74432

Gnomad4 AFR AF: 0.0783

Gnomad4 AMR AF: 0.0125

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.00297 Hom.: 23

Bravo AF: 0.0272

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0738 AC: 325

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00656 AC: 796

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

TNF receptor-associated periodic fever syndrome (TRAPS) Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2019	This variant is associated with the following publications: (PMID: 16569687, 24393624, 11443543, 27872575, 21420073, 20981092, 23894535, 24233262, 27884173) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2022	- -

Autoinflammatory syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;.;D;.
Eigen	Benign	-0.085
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.75	T;T;T;T;T
MetaRNN	Benign	0.0027	T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.5	M;.;M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.9	D;D;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0060	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;.;D;.;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.47
MVP		0.89
MPC		0.79
ClinPred		0.063	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.96

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: rs4149637; hg19: chr12-6443001;