3-48466276-C-T

Position:

• chr3-48466276-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_033629.6(TREX1):​c.-60C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 648,980 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0071 (15 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (51 hom.)
• Consequence: TREX1 NM_033629.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.648

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-48466276-C-T is Benign according to our data. Variant chr3-48466276-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 345770.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00709 (1079/152260) while in subpopulation AFR AF= 0.0214 (891/41548). AF 95% confidence interval is 0.0203. There are 15 homozygotes in gnomad4. There are 537 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREX1	NM_033629.6	c.-60C>T		5_prime_UTR_variant	1/2	ENST00000625293.3	NP_338599.1
ATRIP	NM_130384.3	c.*722C>T		3_prime_UTR_variant	13/13	ENST00000320211.10	NP_569055.1
ATRIP-TREX1	NR_153405.1	n.3250C>T		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TREX1	ENST00000625293.3	c.-60C>T		5_prime_UTR_variant	1/2		NM_033629.6	ENSP00000486676	P1
ATRIP	ENST00000320211.10	c.*722C>T		3_prime_UTR_variant	13/13	1	NM_130384.3	ENSP00000323099	P1

Frequencies

GnomAD3 genomes AF: 0.00707 AC: 1075 AN: 152142 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0214

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0209

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00574

GnomAD4 exome AF: 0.00422 AC: 2098 AN: 496720 Hom.: 51 Cov.: 6 AF XY: 0.00393 AC XY: 1028 AN XY: 261650

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.00218

Gnomad4 ASJ exome AF: 0.000604

Gnomad4 EAS exome AF: 0.0499

Gnomad4 SAS exome AF: 0.000689

Gnomad4 FIN exome AF: 0.000118

Gnomad4 NFE exome AF: 0.000304

Gnomad4 OTH exome AF: 0.00329

GnomAD4 genome AF: 0.00709 AC: 1079 AN: 152260 Hom.: 15 Cov.: 33 AF XY: 0.00721 AC XY: 537 AN XY: 74436

Gnomad4 AFR AF: 0.0214

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0209

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.000267 Hom.: 0

Bravo AF: 0.00764

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Aicardi-Goutieres syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.8
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2279076; hg19: chr3-48507675;