3-142555897-AT-ATT

Position:

• chr3-142555897-AT-ATT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001184.4(ATR):​c.2320_2321insA​(p.Ile774AsnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,463,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: ATR NM_001184.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-142555897-A-AT is Pathogenic according to our data. Variant chr3-142555897-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 938417.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.2320_2321insA	p.Ile774AsnfsTer3	frameshift_variant	10/47	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.2320_2321insA	p.Ile774AsnfsTer3	frameshift_variant	10/47	1	NM_001184.4	ENSP00000343741	P1

Frequencies

GnomAD3 genomes AF: 0.0000399 AC: 6 AN: 150366 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000488

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: 0.0000980

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00107 AC: 1404 AN: 1312876 Hom.: 0 Cov.: 31 AF XY: 0.00106 AC XY: 691 AN XY: 652768

Gnomad4 AFR exome AF: 0.00196

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.00132

Gnomad4 EAS exome AF: 0.000930

Gnomad4 SAS exome AF: 0.00213

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.000858

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.0000399 AC: 6 AN: 150366 Hom.: 0 Cov.: 32 AF XY: 0.0000409 AC XY: 3 AN XY: 73330

Gnomad4 AFR AF: 0.0000488

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000980

Gnomad4 NFE AF: 0.0000444

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2022	Identified in the germline of a patient with colorectal cancer in the literature (Bertelsen et al., 2019) who also had a variant in another gene associated with cancer; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31263571) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 14, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 938417). This variant has not been reported in the literature in individuals affected with ATR-related conditions. 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.Ile774Asnfs*3) 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). -

Seckel syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;