12-6328979-C-T

Variant names:

• chr12-6328979-C-T
• rs4149646
• NM_001065.4:c.*333G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001065.4(TNFRSF1A):​c.*333G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 352,354 control chromosomes in the GnomAD database, including 521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (450 hom., cov: 33)
  • Exomes 𝑓: 0.0069 (71 hom.)
• Consequence: TNFRSF1A NM_001065.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0650
• Publications: 4 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]

PLEKHG6 (HGNC:25562): (pleckstrin homology and RhoGEF domain containing G6) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of small GTPase mediated signal transduction. Located in cell junction and centrosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-6328979-C-T is Benign according to our data. Variant chr12-6328979-C-T is described in ClinVar as Benign. ClinVar VariationId is 310101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

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.*333G>A		3_prime_UTR	Exon 10 of 10	NP_001056.1	P19438-1
	TNFRSF1A	NM_001346091.2		c.*333G>A		3_prime_UTR	Exon 9 of 9	NP_001333020.1	P19438-2
	TNFRSF1A	NM_001346092.2		c.*333G>A		3_prime_UTR	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.*333G>A		3_prime_UTR	Exon 10 of 10	ENSP00000162749.2	P19438-1
	TNFRSF1A	ENST00000366159.9	TSL:1	n.2802G>A		non_coding_transcript_exon	Exon 10 of 10
	TNFRSF1A	ENST00000534885.5	TSL:1	n.*1178G>A		non_coding_transcript_exon	Exon 9 of 9	ENSP00000441803.1	F5GWJ4

Frequencies

GnomAD3 genomes AF: 0.0430 AC: 6543 AN: 152198 Hom.: 446 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0207

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.0420

GnomAD4 exome AF: 0.00686 AC: 1372 AN: 200038 Hom.: 71 Cov.: 0 AF XY: 0.00559 AC XY: 565 AN XY: 101034

African (AFR) AF: 0.141 AC: 852 AN: 6060

American (AMR) AF: 0.0171 AC: 103 AN: 6010

Ashkenazi Jewish (ASJ) AF: 0.00628 AC: 49 AN: 7798

East Asian (EAS) AF: 0.00 AC: 0 AN: 18268

South Asian (SAS) AF: 0.00 AC: 0 AN: 2208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16442

Middle Eastern (MID) AF: 0.00370 AC: 4 AN: 1080

European-Non Finnish (NFE) AF: 0.000856 AC: 110 AN: 128568

Other (OTH) AF: 0.0187 AC: 254 AN: 13604

GnomAD4 genome AF: 0.0430 AC: 6556 AN: 152316 Hom.: 450 Cov.: 33 AF XY: 0.0420 AC XY: 3131 AN XY: 74496

African (AFR) AF: 0.146 AC: 6079 AN: 41538

American (AMR) AF: 0.0206 AC: 315 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000661 AC: 45 AN: 68038

Other (OTH) AF: 0.0416 AC: 88 AN: 2116

Alfa AF: 0.0412 Hom.: 271

Bravo AF: 0.0498

Asia WGS AF: 0.00751 AC: 26 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.9
DANN	Benign	0.77
PhyloP100		-0.065
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4149646; hg19: chr12-6438145;