rs2229032

Positions:

• chr3-142459302-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001184.4(ATR):​c.7274G>A​(p.Arg2425Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,772 control chromosomes in the GnomAD database, including 18,203 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1344 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16859 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0370

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]

ATR (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATR. . Gene score misZ 4.3648 (greater than the threshold 3.09). Trascript score misZ 7.1274 (greater than threshold 3.09). GenCC has associacion of gene with sarcoma, Seckel syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Seckel syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.001532197).
• BP6: Variant 3-142459302-C-T is Benign according to our data. Variant chr3-142459302-C-T is described in ClinVar as [Benign]. Clinvar id is 136470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142459302-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATR	NM_001184.4	c.7274G>A	p.Arg2425Gln	missense_variant	43/47	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.7274G>A	p.Arg2425Gln	missense_variant	43/47	1	NM_001184.4	ENSP00000343741.4

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19374 AN: 152002 Hom.: 1340 Cov.: 32

Gnomad AFR AF: 0.0810

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0845

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0982

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.131 AC: 32811 AN: 251230 Hom.: 2377 AF XY: 0.131 AC XY: 17833 AN XY: 135798

Gnomad AFR exome AF: 0.0795

Gnomad AMR exome AF: 0.0994

Gnomad ASJ exome AF: 0.0798

Gnomad EAS exome AF: 0.0982

Gnomad SAS exome AF: 0.0957

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.149 AC: 217372 AN: 1461652 Hom.: 16859 Cov.: 34 AF XY: 0.147 AC XY: 106950 AN XY: 727134

Gnomad4 AFR exome AF: 0.0736

Gnomad4 AMR exome AF: 0.101

Gnomad4 ASJ exome AF: 0.0794

Gnomad4 EAS exome AF: 0.114

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.167

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.138

GnomAD4 genome AF: 0.127 AC: 19375 AN: 152120 Hom.: 1344 Cov.: 32 AF XY: 0.125 AC XY: 9319 AN XY: 74358

Gnomad4 AFR AF: 0.0808

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0845

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.0989

Gnomad4 FIN AF: 0.163

Gnomad4 NFE AF: 0.160

Gnomad4 OTH AF: 0.137

Alfa AF: 0.148 Hom.: 4225

Bravo AF: 0.120

TwinsUK AF: 0.161 AC: 597

ALSPAC AF: 0.147 AC: 568

ESP6500AA AF: 0.0881 AC: 388

ESP6500EA AF: 0.158 AC: 1357

ExAC AF: 0.133 AC: 16083

Asia WGS AF: 0.0990 AC: 347 AN: 3478

EpiCase AF: 0.155

EpiControl AF: 0.150

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 27, 2016	Variant summary: The c.7274G>A variant involves the alteration of a non-conserved nucleotide and 4/4 in silico tools predict a neutral outcome. The variant was observed in the large, broad control population, ExAC, with an allele frequency of 13.3% which includes 1212 homozygous occurrences, strong evidence this variant is a benign polymorphism. The variant has been reported as benign by multiple reputable clinical labs/publications. Taken together, this variant has been classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome Benign:2

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

Seckel syndrome 1 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.68
DANN	Benign	0.84
DEOGEN2	Benign	0.053	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.17
Sift	Benign	0.56	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.022
MPC		0.72
ClinPred		0.0046	T
GERP RS		-9.1
Varity_R		0.046
gMVP		0.072

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: rs2229032; hg19: chr3-142178144; COSMIC: COSV63383988; COSMIC: COSV63383988;