12-6328961-C-CA

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001065.4(TNFRSF1A):c.*350_*351insT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00978 in 303,608 control chromosomes in the GnomAD database, including 47 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (41 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (6 hom.)
• Consequence: TNFRSF1A NM_001065.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.199

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 -10 ACMG points.

• BP6: Variant 12-6328961-C-CA is Benign according to our data. Variant chr12-6328961-C-CA is described in ClinVar as [Likely_benign]. Clinvar id is 310100.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0147 (2229/152058) while in subpopulation AFR AF= 0.0387 (1608/41502). AF 95% confidence interval is 0.0372. There are 41 homozygotes in gnomad4. There are 1082 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 2211 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF1A	NM_001065.4	c.*350_*351insT		3_prime_UTR_variant	10/10	ENST00000162749.7
TNFRSF1A	NM_001346091.2	c.*350_*351insT		3_prime_UTR_variant	9/9
TNFRSF1A	NM_001346092.2	c.*350_*351insT		3_prime_UTR_variant	11/11
TNFRSF1A	NR_144351.2	n.1906_1907insT		non_coding_transcript_exon_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1A	ENST00000162749.7	c.*350_*351insT		3_prime_UTR_variant	10/10	1	NM_001065.4	P1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2211 AN: 151940 Hom.: 39 Cov.: 33

Gnomad AFR AF: 0.0384

Gnomad AMI AF: 0.0495

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.00759

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00400

Gnomad OTH AF: 0.00766

GnomAD4 exome AF: 0.00488 AC: 740 AN: 151550 Hom.: 6 Cov.: 0 AF XY: 0.00454 AC XY: 346 AN XY: 76152

Gnomad4 AFR exome AF: 0.0371

Gnomad4 AMR exome AF: 0.00593

Gnomad4 ASJ exome AF: 0.00326

Gnomad4 EAS exome AF: 0.000291

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.00554

Gnomad4 NFE exome AF: 0.00346

Gnomad4 OTH exome AF: 0.00739

GnomAD4 genome AF: 0.0147 AC: 2229 AN: 152058 Hom.: 41 Cov.: 33 AF XY: 0.0146 AC XY: 1082 AN XY: 74326

Gnomad4 AFR AF: 0.0387

Gnomad4 AMR AF: 0.00720

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.00759

Gnomad4 NFE AF: 0.00400

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00569 Hom.: 1

Bravo AF: 0.0152

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial Periodic Fever Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs201099296; hg19: chr12-6438127;