rs28897765

Variant names:

• chr3-142561266-T-C
• rs28897765
• NM_001184.4:c.1326A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001184.4(ATR):​c.1326A>G​(p.Lys442Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,613,898 control chromosomes in the GnomAD database, including 400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (30 hom., cov: 32)
  • Exomes 𝑓: 0.020 (370 hom.)
• Consequence: ATR NM_001184.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.327
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• Seckel syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome

  Inheritance: Unknown, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• Seckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• familial prostate carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-142561266-T-C is Benign according to our data. Variant chr3-142561266-T-C is described in ClinVar as Benign. ClinVar VariationId is 157962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.327 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.018 (2744/152228) while in subpopulation SAS AF = 0.0411 (198/4822). AF 95% confidence interval is 0.0364. There are 30 homozygotes in GnomAd4. There are 1289 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4	c.1326A>G	p.Lys442Lys	synonymous_variant	Exon 5 of 47	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.1326A>G	p.Lys442Lys	synonymous_variant	Exon 5 of 47	1	NM_001184.4	ENSP00000343741.4

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2743 AN: 152110 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0414

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.0182 AC: 4584 AN: 251452 AF XY: 0.0197

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0198 AC: 28998 AN: 1461670 Hom.: 370 Cov.: 31 AF XY: 0.0204 AC XY: 14851 AN XY: 727144

African (AFR) AF: 0.0209 AC: 698 AN: 33474

American (AMR) AF: 0.0114 AC: 509 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0307 AC: 802 AN: 26130

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39674

South Asian (SAS) AF: 0.0412 AC: 3553 AN: 86250

European-Finnish (FIN) AF: 0.00376 AC: 201 AN: 53418

Middle Eastern (MID) AF: 0.0378 AC: 218 AN: 5766

European-Non Finnish (NFE) AF: 0.0195 AC: 21640 AN: 1111850

Other (OTH) AF: 0.0227 AC: 1371 AN: 60386

GnomAD4 genome AF: 0.0180 AC: 2744 AN: 152228 Hom.: 30 Cov.: 32 AF XY: 0.0173 AC XY: 1289 AN XY: 74444

African (AFR) AF: 0.0219 AC: 910 AN: 41540

American (AMR) AF: 0.0127 AC: 194 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0411 AC: 198 AN: 4822

European-Finnish (FIN) AF: 0.00283 AC: 30 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0185 AC: 1255 AN: 67996

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.0198 Hom.: 12

Bravo AF: 0.0181

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.0224

EpiControl AF: 0.0200

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Apr 27, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.1326A>G variant affects a non-conserved nucleotide, resulting in a synonymous mutation. Mutation taster predicts benign outcome for this variant along with 4/5 in silico tools via Alamut predicting the variant not to have an impact on normal splicing. This variant is found in 2299/121410 control chromosomes (48 homozygotes) at a frequency of 0.0189358, which is about 30297 times of the maximal expected frequency of a pathogenic allele (0.0000006), suggesting this variant is benign. In addition, a clinical laboratory classifies this variant as benign (without evidence to independently evaluate). Taken together, this variant was classified as Benign.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATR: BP4, BP7, BS1, BS2

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Seckel syndrome 1 Benign:2

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 specified Benign:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.4
DANN	Benign	0.46
PhyloP100		0.33
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28897765; hg19: chr3-142280108; COSMIC: COSV63385670;