12-6328935-A-AAAAAC

Variant names:

• chr12-6328935-A-AAAAAC
• rs554776242
• NM_001065.4:c.*372_*376dupGTTTT

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001065.4(TNFRSF1A):​c.*372_*376dupGTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 239,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: TNFRSF1A NM_001065.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.589
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00025 (38/152218) while in subpopulation SAS AF = 0.000414 (2/4832). AF 95% confidence interval is 0.000267. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 38 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.*372_*376dupGTTTT		3_prime_UTR	Exon 10 of 10	NP_001056.1	P19438-1
	TNFRSF1A	NM_001346091.2		c.*372_*376dupGTTTT		3_prime_UTR	Exon 9 of 9	NP_001333020.1	P19438-2
	TNFRSF1A	NM_001346092.2		c.*372_*376dupGTTTT		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.*372_*376dupGTTTT		3_prime_UTR	Exon 10 of 10	ENSP00000162749.2	P19438-1
	TNFRSF1A	ENST00000366159.9	TSL:1	n.2841_2845dupGTTTT		non_coding_transcript_exon	Exon 10 of 10
	TNFRSF1A	ENST00000534885.5	TSL:1	n.*1217_*1221dupGTTTT		non_coding_transcript_exon	Exon 9 of 9	ENSP00000441803.1	F5GWJ4

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000285 AC: 25 AN: 87744 Hom.: 0 Cov.: 0 AF XY: 0.000228 AC XY: 10 AN XY: 43782

African (AFR) AF: 0.00 AC: 0 AN: 3246

American (AMR) AF: 0.00 AC: 0 AN: 2496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3750

East Asian (EAS) AF: 0.00 AC: 0 AN: 7784

South Asian (SAS) AF: 0.00 AC: 0 AN: 924

European-Finnish (FIN) AF: 0.000185 AC: 1 AN: 5416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 494

European-Non Finnish (NFE) AF: 0.000400 AC: 23 AN: 57446

Other (OTH) AF: 0.000162 AC: 1 AN: 6188

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152218 Hom.: 0 Cov.: 33 AF XY: 0.000202 AC XY: 15 AN XY: 74368

African (AFR) AF: 0.000193 AC: 8 AN: 41440

American (AMR) AF: 0.000131 AC: 2 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000163 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Familial Periodic Fever (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.59

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs554776242; hg19: chr12-6438101;