rs587777852

Positions:

• chr3-142465860-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The ENST00000350721.9(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: ATR ENST00000350721.9 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.0550

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 3-142465860-G-C is Pathogenic according to our data. Variant chr3-142465860-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 156537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATR	NM_001184.4	c.6897+464C>G		intron_variant		ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.6897+464C>G		intron_variant		1	NM_001184.4	ENSP00000343741	P1
	ENST00000460977.1	n.269-49C>G		intron_variant, non_coding_transcript_variant		3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000835

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.0000726

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000102

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ATR: PM3, PS3:Moderate, PM2:Supporting, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	This sequence change falls in intron 40 of the ATR gene. It does not directly change the encoded amino acid sequence of the ATR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587777852, gnomAD 0.007%). This variant has been observed in individuals with Seckel syndrome (PMID: 23144622). ClinVar contains an entry for this variant (Variation ID: 156537). 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 introduces a premature termination codon (PMID: 23144622). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

ATR-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 02, 2024

The ATR c.6897+464C>G variant is predicted to interfere with splicing. This variant has been reported with a second ATR variant in two individuals with Seckel syndrome (Ogi et al. 2012. PubMed ID: 23144622). RT-PCR studies suggest this variant impacts mRNA splicing (Ogi et al. 2012. PubMed ID: 23144622). This variant is reported in 0.013% of alleles in individuals of European (non-Finnish) descent in gnomAD and is reported as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/156537/). We interpret this variant as likely pathogenic. -

Seckel syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	23
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs587777852; hg19: chr3-142184702;