chr16-3676159-A-G

Variant names:

• chr16-3676159-A-G
• rs8050400
• NM_016292.3:c.705-14T>C

Variant summary

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

The NM_016292.3(TRAP1):​c.705-14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.908 in 1,611,058 control chromosomes in the GnomAD database, including 665,294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66318 hom., cov: 32)
  • Exomes 𝑓: 0.91 (598976 hom.)
• Consequence: TRAP1 NM_016292.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.548
• Publications: 14 publications found

Genes affected

TRAP1 (HGNC:16264): (TNF receptor associated protein 1) This gene encodes a mitochondrial chaperone protein that is member of the heat shock protein 90 (HSP90) family. The encoded protein has ATPase activity and interacts with tumor necrosis factor type I. This protein may function in regulating cellular stress responses. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

LOC124903630 (HGNC:):

DNASE1 (HGNC:2956): (deoxyribonuclease 1) This gene encodes a member of the DNase family. This protein is stored in the zymogen granules of the nuclear envelope and functions by cleaving DNA in an endonucleolytic manner. At least six autosomal codominant alleles have been characterized, DNASE1*1 through DNASE1*6, and the sequence of DNASE1*2 represented in this record. Mutations in this gene have been associated with systemic lupus erythematosus (SLE), an autoimmune disease. A recombinant form of this protein is used to treat the one of the symptoms of cystic fibrosis by hydrolyzing the extracellular DNA in sputum and reducing its viscosity. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

DNASE1 Gene-Disease associations (from GenCC):

• autosomal systemic lupus erythematosus type 16

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-3676159-A-G is Benign according to our data. Variant chr16-3676159-A-G is described in ClinVar as Benign. ClinVar VariationId is 260709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016292.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAP1	NM_016292.3	MANE Select	c.705-14T>C		intron	N/A	NP_057376.2
	TRAP1	NM_001272049.2		c.546-14T>C		intron	N/A	NP_001258978.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRAP1	ENST00000246957.10	TSL:1 MANE Select	c.705-14T>C		intron	N/A	ENSP00000246957.5
	TRAP1	ENST00000575671.5	TSL:1	c.78-14T>C		intron	N/A	ENSP00000458166.1
	TRAP1	ENST00000570514.5	TSL:2	n.56T>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.932 AC: 141829 AN: 152166 Hom.: 66255 Cov.: 32

Gnomad AFR AF: 0.981

Gnomad AMI AF: 0.951

Gnomad AMR AF: 0.942

Gnomad ASJ AF: 0.948

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.981

Gnomad FIN AF: 0.916

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.893

Gnomad OTH AF: 0.928

GnomAD2 exomes AF: 0.932 AC: 231876 AN: 248890 AF XY: 0.931

Gnomad AFR exome AF: 0.983

Gnomad AMR exome AF: 0.960

Gnomad ASJ exome AF: 0.941

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.911

Gnomad NFE exome AF: 0.894

Gnomad OTH exome AF: 0.924

GnomAD4 exome AF: 0.906 AC: 1321041 AN: 1458774 Hom.: 598976 Cov.: 33 AF XY: 0.908 AC XY: 658997 AN XY: 725738

African (AFR) AF: 0.985 AC: 32839 AN: 33336

American (AMR) AF: 0.957 AC: 42206 AN: 44106

Ashkenazi Jewish (ASJ) AF: 0.940 AC: 24455 AN: 26016

East Asian (EAS) AF: 1.00 AC: 39626 AN: 39630

South Asian (SAS) AF: 0.982 AC: 84314 AN: 85830

European-Finnish (FIN) AF: 0.907 AC: 48369 AN: 53354

Middle Eastern (MID) AF: 0.962 AC: 5531 AN: 5750

European-Non Finnish (NFE) AF: 0.890 AC: 988245 AN: 1110476

Other (OTH) AF: 0.920 AC: 55456 AN: 60276

GnomAD4 genome AF: 0.932 AC: 141951 AN: 152284 Hom.: 66318 Cov.: 32 AF XY: 0.935 AC XY: 69584 AN XY: 74456

African (AFR) AF: 0.981 AC: 40789 AN: 41572

American (AMR) AF: 0.942 AC: 14412 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.948 AC: 3290 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5164 AN: 5166

South Asian (SAS) AF: 0.981 AC: 4735 AN: 4828

European-Finnish (FIN) AF: 0.916 AC: 9708 AN: 10602

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.893 AC: 60736 AN: 68022

Other (OTH) AF: 0.929 AC: 1962 AN: 2112

Alfa AF: 0.936 Hom.: 18533

Bravo AF: 0.936

Asia WGS AF: 0.990 AC: 3442 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 13, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 87. Only high quality variants are reported.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.55
PhyloP100		0.55
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: rs8050400; hg19: chr16-3726160; COSMIC: COSV55916788; COSMIC: COSV55916788;