rs74876396

Variant names:

• chr3-48467047-T-TCCCCCTGCTCCAAGCA
• rs74876396
• NM_033629.6:c.393_408dupCCCCCTGCTCCAAGCA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_033629.6(TREX1):​c.393_408dupCCCCCTGCTCCAAGCA​(p.Glu137ProfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TREX1 NM_033629.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 1.40
• Publications: 3 publications found

Genes affected

TREX1 (HGNC:12269): (three prime repair exonuclease 1) This gene encodes a nuclear protein with 3' exonuclease activity. The encoded protein may play a role in DNA repair and serve as a proofreading function for DNA polymerase. Mutations in this gene result in Aicardi-Goutieres syndrome, chilblain lupus, Cree encephalitis, and other diseases of the immune system. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2012]

ATRIP (HGNC:33499): (ATR interacting protein) This gene encodes an essential component of the DNA damage checkpoint. The encoded protein binds to single-stranded DNA coated with replication protein A. The protein also interacts with the ataxia telangiectasia and Rad3 related protein kinase, resulting in its accumulation at intranuclear foci induced by DNA damage. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2012]

ATRIP Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: MODERATE Submitted by: G2P
• Seckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary breast carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ATRIP-TREX1 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 39 pathogenic variants in the truncated region.
• PP5: Variant 3-48467047-T-TCCCCCTGCTCCAAGCA is Pathogenic according to our data. Variant chr3-48467047-T-TCCCCCTGCTCCAAGCA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 126387.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033629.6. 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
	TREX1	NM_033629.6	MANE Select	c.393_408dupCCCCCTGCTCCAAGCA	p.Glu137ProfsTer24	frameshift	Exon 2 of 2	NP_338599.1	Q9NSU2-3
	ATRIP	NM_130384.3	MANE Select	c.*1494_*1509dupCCCCCTGCTCCAAGCA		3_prime_UTR	Exon 13 of 13	NP_569055.1	Q8WXE1-1
	TREX1	NM_007248.5		c.363_378dupCCCCCTGCTCCAAGCA	p.Glu127ProfsTer24	frameshift	Exon 2 of 2	NP_009179.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREX1	ENST00000625293.3	TSL:6 MANE Select	c.393_408dupCCCCCTGCTCCAAGCA	p.Glu137ProfsTer24	frameshift	Exon 2 of 2	ENSP00000486676.2	Q9NSU2-3
	TREX1	ENST00000444177.1	TSL:1	c.363_378dupCCCCCTGCTCCAAGCA	p.Glu127ProfsTer24	frameshift	Exon 2 of 2	ENSP00000415972.1	Q9NSU2-2
	TREX1	ENST00000433541.1	TSL:1	c.-25_-10dupCCCCCTGCTCCAAGCA		5_prime_UTR	Exon 4 of 4	ENSP00000412404.1	C9J052

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Aicardi-Goutieres syndrome 1 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs74876396; hg19: chr3-48508446;