rs2227932

chr3-142498695-A-Gchr3-142498695-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001184.4(ATR):c.5460T>C(p.Tyr1820=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,613,800 control chromosomes in the GnomAD database, including 10,072 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (672 hom., cov: 31)
  • Exomes 𝑓: 0.11 (9400 hom.)
• Consequence: ATR NM_001184.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.50

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 3-142498695-A-G is Benign according to our data. Variant chr3-142498695-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142498695-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATR	NM_001184.4	c.5460T>C	p.Tyr1820=	synonymous_variant	32/47	ENST00000350721.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATR	ENST00000350721.9	c.5460T>C	p.Tyr1820=	synonymous_variant	32/47	1	NM_001184.4	P1

Frequencies

GnomAD3 genomes AF: 0.0787 AC: 11966 AN: 152132 Hom.: 669 Cov.: 31

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.0812

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.0736

GnomAD3 exomes AF: 0.0922 AC: 23126 AN: 250950 Hom.: 1357 AF XY: 0.0992 AC XY: 13454 AN XY: 135638

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.0401

Gnomad ASJ exome AF: 0.0794

Gnomad EAS exome AF: 0.00136

Gnomad SAS exome AF: 0.161

Gnomad FIN exome AF: 0.127

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0872

GnomAD4 exome AF: 0.108 AC: 157739 AN: 1461550 Hom.: 9400 Cov.: 32 AF XY: 0.110 AC XY: 79853 AN XY: 727062

Gnomad4 AFR exome AF: 0.0152

Gnomad4 AMR exome AF: 0.0432

Gnomad4 ASJ exome AF: 0.0804

Gnomad4 EAS exome AF: 0.000806

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.128

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.0980

GnomAD4 genome AF: 0.0786 AC: 11972 AN: 152250 Hom.: 672 Cov.: 31 AF XY: 0.0782 AC XY: 5825 AN XY: 74444

Gnomad4 AFR AF: 0.0197

Gnomad4 AMR AF: 0.0582

Gnomad4 ASJ AF: 0.0812

Gnomad4 EAS AF: 0.00308

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.0724

Alfa AF: 0.0986 Hom.: 771

Bravo AF: 0.0669

Asia WGS AF: 0.0670 AC: 233 AN: 3478

EpiCase AF: 0.0993

EpiControl AF: 0.103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Seckel syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	9.1
Dann	Benign	0.88

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: rs2227932; hg19: chr3-142217537; COSMIC: COSV100637634;