rs757500301

chr3-142555897-AT-Achr3-142555897-AT-ATTchr3-142555897-AT-ATTTTTTTT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_001184.4(ATR):c.2320del(p.Ile774TyrfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,504,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ATR NM_001184.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 0.199

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATR	NM_001184.4	c.2320del	p.Ile774TyrfsTer5	frameshift_variant	10/47	ENST00000350721.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATR	ENST00000350721.9	c.2320del	p.Ile774TyrfsTer5	frameshift_variant	10/47	1	NM_001184.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000399 AC: 6 AN: 150370 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000976

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000148 AC: 200 AN: 1354388 Hom.: 0 Cov.: 31 AF XY: 0.000156 AC XY: 105 AN XY: 673206

Gnomad4 AFR exome AF: 0.000424

Gnomad4 AMR exome AF: 0.000945

Gnomad4 ASJ exome AF: 0.000297

Gnomad4 EAS exome AF: 0.0000273

Gnomad4 SAS exome AF: 0.000479

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.0000811

Gnomad4 OTH exome AF: 0.000180

GnomAD4 genome AF: 0.0000399 AC: 6 AN: 150370 Hom.: 0 Cov.: 32 AF XY: 0.0000273 AC XY: 2 AN XY: 73330

Gnomad4 AFR AF: 0.0000976

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00402 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 23, 2022

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Ile774Tyrfs*5) in the ATR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATR are known to be pathogenic (PMID: 21228398, 23144622). This variant has not been reported in the literature in individuals affected with ATR-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 376356). -

Endometrium neoplasm Other:1

not provided, no classification provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs757500301; hg19: chr3-142274739;