rs587783330

chr3-142513486-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001184.4(ATR):c.4641+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000603 in 1,612,792 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (6 hom.)
• Consequence: ATR NM_001184.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.367

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_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATR	NM_001184.4	c.4641+15C>T		intron_variant		ENST00000350721.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATR	ENST00000350721.9	c.4641+15C>T		intron_variant		1	NM_001184.4	P1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000752 AC: 189 AN: 251236 Hom.: 1 AF XY: 0.000736 AC XY: 100 AN XY: 135780

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000784

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000775

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000613 AC: 895 AN: 1460514 Hom.: 6 Cov.: 30 AF XY: 0.000628 AC XY: 456 AN XY: 726680

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.00364

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000708

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000561

Gnomad4 OTH exome AF: 0.000945

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33 AN XY: 74472

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.000570

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Seckel syndrome 1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 01, 2019	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	8.3
Dann	Benign	0.57

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: rs200619976; hg19: chr3-142232328;