3-48466268-T-C

Position:

• chr3-48466268-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033629.6(TREX1):​c.-68T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 618,612 control chromosomes in the GnomAD database, including 9,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1894 hom., cov: 33)
  • Exomes 𝑓: 0.18 (7866 hom.)
• Consequence: TREX1 NM_033629.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.43

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-TREX1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-48466268-T-C is Benign according to our data. Variant chr3-48466268-T-C is described in ClinVar as [Benign]. Clinvar id is 345769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48466268-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.198 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREX1	NM_033629.6	c.-68T>C		5_prime_UTR_variant	1/2	ENST00000625293.3	NP_338599.1
ATRIP	NM_130384.3	c.*714T>C		3_prime_UTR_variant	13/13	ENST00000320211.10	NP_569055.1
ATRIP-TREX1	NR_153405.1	n.3242T>C		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TREX1	ENST00000625293.3	c.-68T>C		5_prime_UTR_variant	1/2		NM_033629.6	ENSP00000486676	P1
ATRIP	ENST00000320211.10	c.*714T>C		3_prime_UTR_variant	13/13	1	NM_130384.3	ENSP00000323099	P1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21215 AN: 151350 Hom.: 1895 Cov.: 33

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.237

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.0393

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.132

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.143

GnomAD4 exome AF: 0.176 AC: 82238 AN: 467144 Hom.: 7866 Cov.: 5 AF XY: 0.178 AC XY: 43666 AN XY: 245802

Gnomad4 AFR exome AF: 0.0391

Gnomad4 AMR exome AF: 0.202

Gnomad4 ASJ exome AF: 0.225

Gnomad4 EAS exome AF: 0.0494

Gnomad4 SAS exome AF: 0.203

Gnomad4 FIN exome AF: 0.136

Gnomad4 NFE exome AF: 0.193

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.140 AC: 21214 AN: 151468 Hom.: 1894 Cov.: 33 AF XY: 0.139 AC XY: 10286 AN XY: 73984

Gnomad4 AFR AF: 0.0367

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.0388

Gnomad4 SAS AF: 0.209

Gnomad4 FIN AF: 0.132

Gnomad4 NFE AF: 0.194

Gnomad4 OTH AF: 0.142

Alfa AF: 0.157 Hom.: 993

Bravo AF: 0.135

Asia WGS AF: 0.115 AC: 398 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Aicardi Goutieres syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.50
DANN	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs3135941; hg19: chr3-48507667;