GeneBe

3-142555897-AT-ATTTTTTTT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001184.4(ATR):​c.2314_2320dupAAAAAAA​(p.Ile774LysfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000736 in 1,358,478 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.4e-7 ( 0 hom. )

Consequence

ATR
NM_001184.4 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.199

Publications

30 publications found
Variant links:
Genes affected
ATR (HGNC:882): (ATR serine/threonine kinase) The protein encoded by this gene is a serine/threonine kinase and DNA damage sensor, activating cell cycle checkpoint signaling upon DNA stress. The encoded protein can phosphorylate and activate several proteins involved in the inhibition of DNA replication and mitosis, and can promote DNA repair, recombination, and apoptosis. This protein is also important for fragile site stability and centrosome duplication. Defects in this gene are a cause of Seckel syndrome 1. [provided by RefSeq, Aug 2017]
ATR Gene-Disease associations (from GenCC):
  • Seckel syndrome 1
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Illumina
  • familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome
    Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
  • sarcoma
    Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
  • Seckel syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • familial prostate carcinoma
    Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
ATR
NM_001184.4
MANE Select
c.2314_2320dupAAAAAAAp.Ile774LysfsTer5
frameshift
Exon 10 of 47NP_001175.2Q13535-1
ATR
NM_001354579.2
c.2122_2128dupAAAAAAAp.Ile710LysfsTer5
frameshift
Exon 9 of 46NP_001341508.1Q13535-2

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
ATR
ENST00000350721.9
TSL:1 MANE Select
c.2314_2320dupAAAAAAAp.Ile774LysfsTer5
frameshift
Exon 10 of 47ENSP00000343741.4Q13535-1
ATR
ENST00000936442.1
c.2161_2167dupAAAAAAAp.Ile723LysfsTer5
frameshift
Exon 9 of 46ENSP00000606501.1
ATR
ENST00000661310.1
c.2122_2128dupAAAAAAAp.Ile710LysfsTer5
frameshift
Exon 9 of 46ENSP00000499589.1Q13535-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.36e-7
AC:
1
AN:
1358478
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
675288
show subpopulations
⚠️ 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:
30748
American (AMR)
AF:
0.00
AC:
0
AN:
40492
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23682
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36774
South Asian (SAS)
AF:
0.00
AC:
0
AN:
77672
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48862
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5372
European-Non Finnish (NFE)
AF:
9.62e-7
AC:
1
AN:
1039062
Other (OTH)
AF:
0.00
AC:
0
AN:
55814
⚠️ 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.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000363
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.20

Splicing

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

Publications

Other links and lift over

dbSNP: rs757500301; hg19: chr3-142274739; API