rs554776242

Variant names:

• chr12-6328935-AAAAACAAAAC-A
• rs554776242
• NM_001065.4:c.*367_*376delGTTTTGTTTT

Your query was ambiguous. Multiple possible variants found:

• chr12-6328935-AAAAACAAAAC-A
• chr12-6328935-AAAAACAAAAC-AAAAAC
• chr12-6328935-AAAAACAAAAC-AAAAACAAAACAAAAC
• chr12-6328935-AAAAACAAAAC-AAAAACAAAACAAAACAAAAC
• chr12-6328935-AAAAACAAAAC-AAAAACAAAACAAAACAAAACAAAAC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001065.4(TNFRSF1A):​c.*367_*376delGTTTTGTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 240,074 control chromosomes in the GnomAD database, including 12 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0031 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: TNFRSF1A NM_001065.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.330
• 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00312 (475/152334) while in subpopulation AMR AF = 0.0278 (425/15300). AF 95% confidence interval is 0.0256. There are 9 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 475 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.*367_*376delGTTTTGTTTT		3_prime_UTR	Exon 10 of 10	NP_001056.1	P19438-1
	TNFRSF1A	NM_001346091.2		c.*367_*376delGTTTTGTTTT		3_prime_UTR	Exon 9 of 9	NP_001333020.1	P19438-2
	TNFRSF1A	NM_001346092.2		c.*367_*376delGTTTTGTTTT		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.*367_*376delGTTTTGTTTT		3_prime_UTR	Exon 10 of 10	ENSP00000162749.2	P19438-1
	TNFRSF1A	ENST00000366159.9	TSL:1	n.2836_2845delGTTTTGTTTT		non_coding_transcript_exon	Exon 10 of 10
	TNFRSF1A	ENST00000534885.5	TSL:1	n.*1212_*1221delGTTTTGTTTT		non_coding_transcript_exon	Exon 9 of 9	ENSP00000441803.1	F5GWJ4

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 474 AN: 152216 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0277

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.00137 AC: 120 AN: 87740 Hom.: 3 AF XY: 0.00119 AC XY: 52 AN XY: 43780

African (AFR) AF: 0.00123 AC: 4 AN: 3246

American (AMR) AF: 0.0385 AC: 96 AN: 2494

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: 0.00 AC: 0 AN: 5416

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

European-Non Finnish (NFE) AF: 0.000104 AC: 6 AN: 57444

Other (OTH) AF: 0.00226 AC: 14 AN: 6188

GnomAD4 genome AF: 0.00312 AC: 475 AN: 152334 Hom.: 9 Cov.: 33 AF XY: 0.00326 AC XY: 243 AN XY: 74494

African (AFR) AF: 0.000722 AC: 30 AN: 41562

American (AMR) AF: 0.0278 AC: 425 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68040

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00597

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism

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;