rs3135946

Positions:

• chr3-48467637-T-C

Variant summary

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

The ENST00000320211.10(ATRIP):​c.*2083T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00778 in 1,595,078 control chromosomes in the GnomAD database, including 620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (314 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (306 hom.)
• Consequence: ATRIP ENST00000320211.10 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.999

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=-0.91).
• BP6: Variant 3-48467637-T-C is Benign according to our data. Variant chr3-48467637-T-C is described in ClinVar as [Benign]. Clinvar id is 345780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TREX1	NM_033629.6	c.*37T>C		3_prime_UTR_variant	2/2	ENST00000625293.3	NP_338599.1
ATRIP	NM_130384.3	c.*2083T>C		3_prime_UTR_variant	13/13	ENST00000320211.10	NP_569055.1
ATRIP-TREX1	NR_153405.1	n.4291T>C		non_coding_transcript_exon_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATRIP	ENST00000320211.10	c.*2083T>C		3_prime_UTR_variant	13/13	1	NM_130384.3	ENSP00000323099	P1
TREX1	ENST00000625293.3	c.*37T>C		3_prime_UTR_variant	2/2		NM_033629.6	ENSP00000486676	P1

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5470 AN: 152166 Hom.: 306 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.0277

GnomAD3 exomes AF: 0.0104 AC: 2368 AN: 226624 Hom.: 112 AF XY: 0.00832 AC XY: 1025 AN XY: 123130

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00805

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000420

Gnomad FIN exome AF: 0.0000497

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00888

GnomAD4 exome AF: 0.00478 AC: 6902 AN: 1442794 Hom.: 306 Cov.: 33 AF XY: 0.00442 AC XY: 3167 AN XY: 715932

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.00934

Gnomad4 ASJ exome AF: 0.0167

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000411

Gnomad4 FIN exome AF: 0.0000586

Gnomad4 NFE exome AF: 0.000938

Gnomad4 OTH exome AF: 0.0114

GnomAD4 genome AF: 0.0362 AC: 5512 AN: 152284 Hom.: 314 Cov.: 33 AF XY: 0.0358 AC XY: 2665 AN XY: 74466

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0156

Gnomad4 ASJ AF: 0.0187

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00160

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0250 Hom.: 76

Bravo AF: 0.0415

Asia WGS AF: 0.0100 AC: 36 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	Aug 07, 2017	- -
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	-0.91
CADD	Benign	0.87
DANN	Benign	0.33

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3135946; hg19: chr3-48509036;