rs12486046

Positions:

• chr3-48465783-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.192

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-TREX1 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 69 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATRIP	NM_130384.3	c.*229A>G		3_prime_UTR_variant	13/13	ENST00000320211.10
ATRIP-TREX1	NR_153405.1	n.2757A>G		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATRIP	ENST00000320211.10	c.*229A>G		3_prime_UTR_variant	13/13	1	NM_130384.3	P1
ATRIP	ENST00000634384.2	c.*229A>G		3_prime_UTR_variant, NMD_transcript_variant	10/11	2
ATRIP	ENST00000635464.1	c.*1006A>G		3_prime_UTR_variant, NMD_transcript_variant	15/16	5
TREX1	ENST00000433541.1			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3838 AN: 152140 Hom.: 69 Cov.: 33

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.: 4 AF XY: 0.0293 AC XY: 5537 AN XY: 189270

Gnomad4 AFR exome AF: 0.00711

Gnomad4 AMR exome AF: 0.0287

Gnomad4 ASJ exome AF: 0.0126

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0201

Gnomad4 FIN exome AF: 0.0275

Gnomad4 NFE exome AF: 0.0372

Gnomad4 OTH exome AF: 0.0256

GnomAD4 genome AF: 0.0252 AC: 3838 AN: 152258 Hom.: 69 Cov.: 33 AF XY: 0.0240 AC XY: 1788 AN XY: 74446

Gnomad4 AFR AF: 0.00804

Gnomad4 AMR AF: 0.0254

Gnomad4 ASJ AF: 0.0136

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.0282

Gnomad4 NFE AF: 0.0382

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0339 Hom.: 43

Bravo AF: 0.0245

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs12486046; hg19: chr3-48507182;