dbSNP rs12486046: ATRIP:c.*229A>G (chr3-48465783-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_130384.3(ATRIP):c.*229A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 507,804 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 69 hom., cov: 33)

Exomes 𝑓: 0.029 ( 184 hom. )

Consequence

ATRIP
NM_130384.3 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.192

Publications

5 publications found

Variant links:

Genes affected

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 links:

ATRIP-TREX1 (HGNC:):

ATRIP-TREX1 links:

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]

TREX1 Gene-Disease associations (from GenCC):

Aicardi-Goutieres syndrome 1
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
TREX1-related type 1 interferonopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
chilblain lupus 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
Aicardi-Goutieres syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial chilblain lupus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

TREX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant 3-48465783-A-G is Benign according to our data. Variant chr3-48465783-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1191674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0252 (3838/152258) while in subpopulation NFE AF = 0.0382 (2601/68024). AF 95% confidence interval is 0.037. There are 69 homozygotes in GnomAd4. There are 1788 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 69 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130384.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATRIP	NM_130384.3	MANE Select	c.*229A>G	3_prime_UTR	Exon 13 of 13	NP_569055.1	Q8WXE1-1
ATRIP	NM_032166.4		c.*229A>G	3_prime_UTR	Exon 12 of 12	NP_115542.2
ATRIP	NM_001271023.2		c.*229A>G	3_prime_UTR	Exon 13 of 13	NP_001257952.1	Q8WXE1-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATRIP	ENST00000320211.10	TSL:1 MANE Select	c.*229A>G	3_prime_UTR	Exon 13 of 13	ENSP00000323099.3	Q8WXE1-1
ATRIP	ENST00000634384.2	TSL:2	n.*229A>G	non_coding_transcript_exon	Exon 10 of 11	ENSP00000489041.2	A0A0U1RQJ8
ATRIP	ENST00000635464.1	TSL:5	n.*1006A>G	non_coding_transcript_exon	Exon 15 of 16	ENSP00000489199.1	A0A0U1RQW3

Frequencies

GnomAD3 genomes

AF:

0.0252

AC:

3838

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00806

Gnomad AMI

AF:

0.0484

Gnomad AMR

AF:

0.0253

Gnomad ASJ

AF:

0.0136

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0180

Gnomad FIN

AF:

0.0282

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0383

Gnomad OTH

AF:

0.0158

GnomAD4 exome

AF:

0.0294

AC:

10460

AN:

355546

Hom.:

184

Cov.:

AF XY:

0.0293

AC XY:

5537

AN XY:

189270

show subpopulations

African (AFR)

AF:

0.00711

AC:

AN:

9982

American (AMR)

AF:

0.0287

AC:

447

AN:

15592

Ashkenazi Jewish (ASJ)

AF:

0.0126

AC:

131

AN:

10422

East Asian (EAS)

AF:

0.00

AC:

AN:

22392

South Asian (SAS)

AF:

0.0201

AC:

903

AN:

44882

European-Finnish (FIN)

AF:

0.0275

AC:

573

AN:

20810

Middle Eastern (MID)

AF:

0.00445

AC:

AN:

1572

European-Non Finnish (NFE)

AF:

0.0372

AC:

7818

AN:

209956

Other (OTH)

AF:

0.0256

AC:

510

AN:

19938

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

505

1010

1515

2020

2525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0252

AC:

3838

AN:

152258

Hom.:

Cov.:

AF XY:

0.0240

AC XY:

1788

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00804

AC:

334

AN:

41548

American (AMR)

AF:

0.0254

AC:

388

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.0182

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0282

AC:

299

AN:

10606

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0382

AC:

2601

AN:

68024

Other (OTH)

AF:

0.0156

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

200

401

601

802

1002

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0332

Hom.:

Bravo

AF:

0.0245

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

0.19

PromoterAI

-0.059

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over