chr3-48466276-C-T

Variant names:

• chr3-48466276-C-T
• rs2279076
• NM_033629.6:c.-60C>T

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.648
• 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR,AD,Unknown gene

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.-60C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	NP_338599.1	Q9NSU2-3
	TREX1	NM_033629.6	MANE Select	c.-60C>T		5_prime_UTR	Exon 1 of 2	NP_338599.1	Q9NSU2-3
	ATRIP	NM_130384.3	MANE Select	c.*722C>T		3_prime_UTR	Exon 13 of 13	NP_569055.1	Q8WXE1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREX1	ENST00000625293.3	TSL:6 MANE Select	c.-60C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000486676.2	Q9NSU2-3
	TREX1	ENST00000433541.1	TSL:1	c.-379C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000412404.1	C9J052
	TREX1	ENST00000625293.3	TSL:6 MANE Select	c.-60C>T		5_prime_UTR	Exon 1 of 2	ENSP00000486676.2	Q9NSU2-3

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

African (AFR) AF: 0.0175 AC: 249 AN: 14252

American (AMR) AF: 0.00218 AC: 55 AN: 25266

Ashkenazi Jewish (ASJ) AF: 0.000604 AC: 9 AN: 14910

East Asian (EAS) AF: 0.0499 AC: 1563 AN: 31352

South Asian (SAS) AF: 0.000689 AC: 35 AN: 50830

European-Finnish (FIN) AF: 0.000118 AC: 4 AN: 33796

Middle Eastern (MID) AF: 0.000945 AC: 2 AN: 2116

European-Non Finnish (NFE) AF: 0.000304 AC: 90 AN: 296522

Other (OTH) AF: 0.00329 AC: 91 AN: 27676

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

African (AFR) AF: 0.0214 AC: 891 AN: 41548

American (AMR) AF: 0.00268 AC: 41 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.0209 AC: 108 AN: 5160

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68006

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.000369 Hom.: 0

Bravo AF: 0.00764

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Aicardi-Goutieres syndrome 1 (1)
-	-	1	Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.8
DANN	Benign	0.79
PhyloP100		-0.65
PromoterAI		0.36	Neutral
Mutation Taster		=299/1	polymorphism

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

Other links and lift over

dbSNP: rs2279076; hg19: chr3-48507675;