3-48465821-T-C

Position:

• chr3-48465821-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000433541.1(TREX1):​c.-522T>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 0.00309 in 415,586 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (7 hom.)
• Consequence: TREX1 ENST00000433541.1 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.13

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 3-48465821-T-C is Benign according to our data. Variant chr3-48465821-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 345761.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00311 (474/152258) while in subpopulation NFE AF= 0.00326 (222/68030). AF 95% confidence interval is 0.00291. There are 4 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATRIP	NM_130384.3	c.*267T>C		3_prime_UTR_variant	13/13	ENST00000320211.10	NP_569055.1
ATRIP-TREX1	NR_153405.1	n.2795T>C		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TREX1	ENST00000433541.1	c.-522T>C		5_prime_UTR_variant	1/4	1		ENSP00000412404
ATRIP	ENST00000320211.10	c.*267T>C		3_prime_UTR_variant	13/13	1	NM_130384.3	ENSP00000323099	P1
ATRIP	ENST00000634384.2	c.*267T>C		3_prime_UTR_variant, NMD_transcript_variant	10/11	2		ENSP00000489041
ATRIP	ENST00000635464.1	c.*1044T>C		3_prime_UTR_variant, NMD_transcript_variant	15/16	5		ENSP00000489199

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 474 AN: 152140 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0227

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00326

Gnomad OTH AF: 0.000956

GnomAD4 exome AF: 0.00308 AC: 811 AN: 263328 Hom.: 7 Cov.: 0 AF XY: 0.00270 AC XY: 379 AN XY: 140540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000372

Gnomad4 ASJ exome AF: 0.000386

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0230

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00206

GnomAD4 genome AF: 0.00311 AC: 474 AN: 152258 Hom.: 4 Cov.: 33 AF XY: 0.00403 AC XY: 300 AN XY: 74452

Gnomad4 AFR AF: 0.0000723

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0227

Gnomad4 NFE AF: 0.00326

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00688 Hom.: 0

Bravo AF: 0.000933

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Aicardi Goutieres syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Benign:1

Likely 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	-0.27
CADD	Benign	19
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs148393533; hg19: chr3-48507220;