rs104895288

Variant names:

• chr12-6333405-T-C
• rs104895288
• NM_001065.4:c.434A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-6333405-T-C
• chr12-6333405-T-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BS1 BS2

The NM_001065.4(TNFRSF1A):​c.434A>G​(p.Asn145Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,613,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: TNFRSF1A NM_001065.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1 O:1
• Conservation: PhyloP100: 2.55
• Publications: 10 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37801474).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000978 (143/1461720) while in subpopulation MID AF = 0.000347 (2/5768). AF 95% confidence interval is 0.0000912. There are 0 homozygotes in GnomAdExome4. There are 74 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 7 AD gene.

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.434A>G	p.Asn145Ser	missense	Exon 4 of 10	NP_001056.1	P19438-1
	TNFRSF1A	NM_001346091.2		c.110A>G	p.Asn37Ser	missense	Exon 3 of 9	NP_001333020.1	P19438-2
	TNFRSF1A	NM_001346092.2		c.-144A>G		5_prime_UTR	Exon 4 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.434A>G	p.Asn145Ser	missense	Exon 4 of 10	ENSP00000162749.2	P19438-1
	TNFRSF1A	ENST00000540022.5	TSL:1	c.305A>G	p.Asn102Ser	missense	Exon 3 of 9	ENSP00000438343.1	F5H061
	TNFRSF1A	ENST00000366159.9	TSL:1	n.468A>G		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000918 AC: 23 AN: 250598 AF XY: 0.0000886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000978 AC: 143 AN: 1461720 Hom.: 0 Cov.: 33 AF XY: 0.000102 AC XY: 74 AN XY: 727160

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000107 AC: 119 AN: 1111960

Other (OTH) AF: 0.0000828 AC: 5 AN: 60396

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000102

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000436

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	1	TNF receptor-associated periodic fever syndrome (TRAPS) (3)
-	1	-	Autoinflammatory syndrome (1)
-	1	-	Febrile seizure (within the age range of 3 months to 6 years);C0019214:Hepatosplenomegaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.5
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.059	T
Polyphen		0.85	P
Vest4		0.36
MVP		0.81
MPC		0.58
ClinPred		0.12	T
GERP RS		0.93
Varity_R		0.33
gMVP		0.94
Mutation Taster		=71/29	polymorphism

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: rs104895288; hg19: chr12-6442571;