NM_001065.4:c.1075C>T

Variant names:

• chr12-6329605-G-A
• rs151344628
• NM_001065.4:c.1075C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001065.4(TNFRSF1A):​c.1075C>T​(p.Leu359Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000633 in 1,593,250 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L359L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: TNFRSF1A NM_001065.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 2.99
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 12-6329605-G-A is Benign according to our data. Variant chr12-6329605-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 97422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000499 (76/152308) while in subpopulation AMR AF = 0.00124 (19/15306). AF 95% confidence interval is 0.000812. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 76 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.1075C>T	p.Leu359Leu	synonymous	Exon 10 of 10	NP_001056.1	P19438-1
	TNFRSF1A	NM_001346091.2		c.751C>T	p.Leu251Leu	synonymous	Exon 9 of 9	NP_001333020.1	P19438-2
	TNFRSF1A	NM_001346092.2		c.616C>T	p.Leu206Leu	synonymous	Exon 11 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.1075C>T	p.Leu359Leu	synonymous	Exon 10 of 10	ENSP00000162749.2	P19438-1
	TNFRSF1A	ENST00000540022.5	TSL:1	c.946C>T	p.Leu316Leu	synonymous	Exon 9 of 9	ENSP00000438343.1	F5H061
	TNFRSF1A	ENST00000366159.9	TSL:1	n.2176C>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.000706

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000572 AC: 127 AN: 222140 AF XY: 0.000454

Gnomad AFR exome AF: 0.000144

Gnomad AMR exome AF: 0.00169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000805

Gnomad NFE exome AF: 0.000599

Gnomad OTH exome AF: 0.00125

GnomAD4 exome AF: 0.000647 AC: 933 AN: 1440942 Hom.: 0 Cov.: 32 AF XY: 0.000626 AC XY: 448 AN XY: 716146

African (AFR) AF: 0.0000604 AC: 2 AN: 33136

American (AMR) AF: 0.00170 AC: 75 AN: 44114

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39320

South Asian (SAS) AF: 0.00 AC: 0 AN: 85684

European-Finnish (FIN) AF: 0.0000246 AC: 1 AN: 40652

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.000739 AC: 818 AN: 1106672

Other (OTH) AF: 0.000619 AC: 37 AN: 59756

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000550 AC XY: 41 AN XY: 74480

African (AFR) AF: 0.000120 AC: 5 AN: 41578

American (AMR) AF: 0.00124 AC: 19 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68002

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000385 Hom.: 0

Bravo AF: 0.000714

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autoinflammatory syndrome (1)
-	-	1	not specified (1)
-	-	1	TNF receptor-associated periodic fever syndrome (TRAPS) (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.7
DANN	Benign	0.95
PhyloP100		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=96/4	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: rs151344628; hg19: chr12-6438771;