3-48466996-G-C

Variant names:

• chr3-48466996-G-C
• rs72556554
• NM_033629.6:c.341G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_033629.6(TREX1):​c.341G>C​(p.Arg114Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R114C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TREX1 NM_033629.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.73
• Publications: 54 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

ATRIP-TREX1 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-48466995-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 209198.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Trascript score misZ: 0.29847 (below the threshold of 3.09). GenCC associations: The gene is linked to Aicardi-Goutieres syndrome 1, Aicardi-Goutieres syndrome, retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, chilblain lupus 1, systemic lupus erythematosus, familial chilblain lupus.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREX1	NM_033629.6	MANE Select	c.341G>C	p.Arg114Pro	missense	Exon 2 of 2	NP_338599.1
	ATRIP	NM_130384.3	MANE Select	c.*1442G>C		3_prime_UTR	Exon 13 of 13	NP_569055.1
	TREX1	NM_007248.5		c.311G>C	p.Arg104Pro	missense	Exon 2 of 2	NP_009179.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREX1	ENST00000625293.3	TSL:6 MANE Select	c.341G>C	p.Arg114Pro	missense	Exon 2 of 2	ENSP00000486676.2
	TREX1	ENST00000444177.1	TSL:1	c.311G>C	p.Arg104Pro	missense	Exon 2 of 2	ENSP00000415972.1
	TREX1	ENST00000433541.1	TSL:1	c.-77G>C		5_prime_UTR	Exon 4 of 4	ENSP00000412404.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.000268 AC: 67 AN: 249654 AF XY: 0.000170

Gnomad AFR exome AF: 0.00290

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000327

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000205 AC: 3 AN: 1460930 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726832

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000571 AC: 3 AN: 52510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000577 AC: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		4.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Vest4		0.77
MVP		0.93
ClinPred		0.16	T
GERP RS		5.0
Varity_R		0.92
gMVP		0.75
Mutation Taster		=172/128	polymorphism

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

Other links and lift over

dbSNP: rs72556554; hg19: chr3-48508395;