rs587777852

Variant names:

• chr3-142465860-G-C
• rs587777852
• NM_001184.4:c.6897+464C>G

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PP3 PP5_Very_Strong

The NM_001184.4(ATR):​c.6897+464C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 170,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV003275192: Studies have shown that this variant alters ATR gene expression (PMID:23144622). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID:23144622)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: ATR NM_001184.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.0550
• Publications: 1 publications found

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

ENSG00000244327 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003275192: Studies have shown that this variant alters ATR gene expression (PMID: 23144622). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 23144622).; SCV005364790: RT-PCR studies suggest this variant impacts mRNA splicing (Ogi et al. 2012. PubMed ID: 23144622).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-142465860-G-C is Pathogenic according to our data. Variant chr3-142465860-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 156537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATR	NM_001184.4	MANE Select	c.6897+464C>G		intron	N/A	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.6705+464C>G		intron	N/A	NP_001341508.1	Q13535-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATR	ENST00000350721.9	TSL:1 MANE Select	c.6897+464C>G		intron	N/A	ENSP00000343741.4	Q13535-1
	ATR	ENST00000513291.2	TSL:1	n.2081+464C>G		intron	N/A
	ATR	ENST00000936442.1		c.6744+464C>G		intron	N/A	ENSP00000606501.1

Frequencies

GnomAD3 genomes AF: 0.0000922 AC: 14 AN: 151840 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000535 AC: 1 AN: 18700 Hom.: 0 Cov.: 0 AF XY: 0.0000974 AC XY: 1 AN XY: 10264

African (AFR) AF: 0.00 AC: 0 AN: 80

American (AMR) AF: 0.00 AC: 0 AN: 1956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 216

East Asian (EAS) AF: 0.00 AC: 0 AN: 776

South Asian (SAS) AF: 0.00 AC: 0 AN: 2244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 28

European-Non Finnish (NFE) AF: 0.0000835 AC: 1 AN: 11980

Other (OTH) AF: 0.00 AC: 0 AN: 854

GnomAD4 genome AF: 0.0000922 AC: 14 AN: 151840 Hom.: 0 Cov.: 31 AF XY: 0.0000674 AC XY: 5 AN XY: 74182

African (AFR) AF: 0.0000726 AC: 3 AN: 41334

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10534

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 67964

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000102

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	ATR-related disorder (1)
1	-	-	Seckel syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	23
DANN	Benign	0.73
PhyloP100		0.055
Mutation Taster		=38/62	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.75		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.75		Position offset: 1

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

Other links and lift over

dbSNP: rs587777852; hg19: chr3-142184702;