chr3-48467637-T-C

Variant names:

• chr3-48467637-T-C
• rs3135946
• NM_130384.3:c.*2083T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_130384.3(ATRIP):​c.*2083T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00778 in 1,595,078 control chromosomes in the GnomAD database, including 620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (314 hom., cov: 33)
  • Exomes 𝑓: 0.0048 (306 hom.)
• Consequence: ATRIP NM_130384.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.999
• Publications: 7 publications found

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]

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-TREX1 (HGNC:):

SHISA5 (HGNC:30376): (shisa family member 5) This gene encodes a member of the shisa family. The encoded protein is localized to the endoplasmic reticulum, and together with p53 induces apoptosis in a caspase-dependent manner. Alternative splicing results in multiple transcript variants. Related pseudogenes of this gene are found on chromosome X. [provided by RefSeq, Apr 2016]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 3-48467637-T-C is Benign according to our data. Variant chr3-48467637-T-C is described in ClinVar as Benign. ClinVar VariationId is 345780.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRIP	NM_130384.3	MANE Select	c.*2083T>C		3_prime_UTR	Exon 13 of 13	NP_569055.1
	TREX1	NM_033629.6	MANE Select	c.*37T>C		3_prime_UTR	Exon 2 of 2	NP_338599.1
	ATRIP-TREX1	NR_153405.1		n.4291T>C		non_coding_transcript_exon	Exon 15 of 15

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATRIP	ENST00000320211.10	TSL:1 MANE Select	c.*2083T>C		3_prime_UTR	Exon 13 of 13	ENSP00000323099.3
	TREX1	ENST00000625293.3	TSL:6 MANE Select	c.*37T>C		3_prime_UTR	Exon 2 of 2	ENSP00000486676.2
	TREX1	ENST00000444177.1	TSL:1	c.*37T>C		3_prime_UTR	Exon 2 of 2	ENSP00000415972.1

Frequencies

GnomAD3 genomes AF: 0.0359 AC: 5470 AN: 152166 Hom.: 306 Cov.: 33

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0156

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00160

Gnomad OTH AF: 0.0277

GnomAD2 exomes AF: 0.0104 AC: 2368 AN: 226624 AF XY: 0.00832

Gnomad AFR exome AF: 0.120

Gnomad AMR exome AF: 0.00805

Gnomad ASJ exome AF: 0.0189

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000497

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00888

GnomAD4 exome AF: 0.00478 AC: 6902 AN: 1442794 Hom.: 306 Cov.: 33 AF XY: 0.00442 AC XY: 3167 AN XY: 715932

African (AFR) AF: 0.128 AC: 4237 AN: 33142

American (AMR) AF: 0.00934 AC: 408 AN: 43660

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 408 AN: 24410

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.000411 AC: 34 AN: 82778

European-Finnish (FIN) AF: 0.0000586 AC: 3 AN: 51234

Middle Eastern (MID) AF: 0.0169 AC: 96 AN: 5664

European-Non Finnish (NFE) AF: 0.000938 AC: 1034 AN: 1102692

Other (OTH) AF: 0.0114 AC: 682 AN: 59648

GnomAD4 genome AF: 0.0362 AC: 5512 AN: 152284 Hom.: 314 Cov.: 33 AF XY: 0.0358 AC XY: 2665 AN XY: 74466

African (AFR) AF: 0.121 AC: 5032 AN: 41542

American (AMR) AF: 0.0156 AC: 238 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

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

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00160 AC: 109 AN: 68016

Other (OTH) AF: 0.0274 AC: 58 AN: 2114

Alfa AF: 0.0264 Hom.: 83

Bravo AF: 0.0415

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 07, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aicardi Goutieres syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.87
DANN	Benign	0.33
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3135946; hg19: chr3-48509036;