rs72556554

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr3-48466996-G-A
• chr3-48466996-G-T
• chr3-48466996-G-C

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM5 PP2 PP3 PP5_Very_Strong

The NM_033629.6(TREX1):​c.341G>A​(p.Arg114His) variant causes a missense change. The variant allele was found at a frequency of 0.00051 in 1,613,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000245673: "In vitro studies suggest that the p.Arg114His variant may lead to a reduction in TREX1 endonuclease activity (de Silva 2007 Lehtinen 2008)"" and additional evidence is available in 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: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: TREX1 NM_033629.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:29 B:1 O:1
• Conservation: PhyloP100: 4.73
• Publications: 56 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: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000245673: "In vitro studies suggest that the p.Arg114His variant may lead to a reduction in TREX1 endonuclease activity (de Silva 2007 Lehtinen 2008)"; SCV000445024: Expression analysis revealed no detectable TREX1 activity in any of the individuals with p.Arg114His (Crow et al. 2006).; SCV000538069: "This variant results in a 50-fold reduction in enzyme activity and is localized to the dimer interface of the protein and is important for dimer stabilization (de Silva et al. 2007)."; SCV003934066: The most pronounced variant effect results in <10% of normal activity (example: Lehtinen_2008).; SCV005399140: "Variant homodimers displayed a 23-fold reduction in enzyme activity (PMID: 21937424)."; SCV000321979: Published functional studies demonstrate the mutant homozygous and compound heterozygous R114H protein has dysfunctional exonuclease activity when compared to the wild type protein (de Silva et al., 2007; Orebaugh et al., 2011; Lehtinen et al., 2008); SCV005413584: PS3; SCV006325622: "In vitro exonuclease degradation assays demonstrate that the abnormal p.Arg114His TREX1 protein homodimer degrades dsDNA ∼300-fold less efficiently than wild-type TREX1 protein." PMID:18805785, PMID:21937424; SCV000819732: Experimental studies have shown that this missense change affects TREX1 function (PMID: 16845398, 17293595, 18805785).; SCV005900660: Functional studies demonstrated that the c.506G>A (p.Arg169His) variant results in a reduction of TREX1 endonuclease activity (PMID: 17293595).
• 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, familial chilblain lupus, chilblain lupus 1, systemic lupus erythematosus, TREX1-related type 1 interferonopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.775
• PP5: Variant 3-48466996-G-A is Pathogenic according to our data. Variant chr3-48466996-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.341G>A	p.Arg114His	missense	Exon 2 of 2	NP_338599.1	Q9NSU2-3
	ATRIP	NM_130384.3	MANE Select	c.*1442G>A		3_prime_UTR	Exon 13 of 13	NP_569055.1	Q8WXE1-1
	TREX1	NM_007248.5		c.311G>A	p.Arg104His	missense	Exon 2 of 2	NP_009179.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TREX1	ENST00000625293.3	TSL:6 MANE Select	c.341G>A	p.Arg114His	missense	Exon 2 of 2	ENSP00000486676.2	Q9NSU2-3
	TREX1	ENST00000444177.1	TSL:1	c.311G>A	p.Arg104His	missense	Exon 2 of 2	ENSP00000415972.1	Q9NSU2-2
	TREX1	ENST00000433541.1	TSL:1	c.-77G>A		5_prime_UTR	Exon 4 of 4	ENSP00000412404.1	C9J052

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000208 AC: 52 AN: 249654 AF XY: 0.000185

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000531 AC: 776 AN: 1460932 Hom.: 0 Cov.: 31 AF XY: 0.000502 AC XY: 365 AN XY: 726832

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000381 AC: 2 AN: 52510

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

European-Non Finnish (NFE) AF: 0.000656 AC: 730 AN: 1111992

Other (OTH) AF: 0.000480 AC: 29 AN: 60364

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152154 Hom.: 0 Cov.: 33 AF XY: 0.000283 AC XY: 21 AN XY: 74316

African (AFR) AF: 0.000265 AC: 11 AN: 41436

American (AMR) AF: 0.000262 AC: 4 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68024

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.000280

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000600

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
13	-	-	not provided (13)
9	-	-	Aicardi-Goutieres syndrome 1 (9)
3	-	-	TREX1-related disorder (3)
2	-	-	Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (2)
-	-	1	Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C0950123:Inborn genetic diseases (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Systemic lupus erythematosus;C0024145:Chilblain lupus 1;C0796126:Aicardi-Goutieres syndrome 1;C1860518:Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (1)
-	-	-	Systemic lupus erythematosus, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Pathogenic	0.92	D
PhyloP100		4.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Vest4		0.80
MVP		0.91
ClinPred		0.52	D
GERP RS		5.0
Varity_R		0.50
gMVP		0.48
Mutation Taster		=172/128	disease causing (ClinVar)

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;