rs28897765

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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:10
• Conservation: PhyloP100: 0.327

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=-0.86).
• BP6: Variant 3-142561266-T-C is Benign according to our data. Variant chr3-142561266-T-C is described in ClinVar as [Benign]. Clinvar id is 157962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142561266-T-C is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 30 AD,AR 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

GnomAD3 exomes AF: 0.0182 AC: 4584 AN: 251452 Hom.: 84 AF XY: 0.0197 AC XY: 2671 AN XY: 135902

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 SAS exome AF: 0.0424

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

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.0114

Gnomad4 ASJ exome AF: 0.0307

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0412

Gnomad4 FIN exome AF: 0.00376

Gnomad4 NFE exome AF: 0.0195

Gnomad4 OTH exome AF: 0.0227

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

Gnomad4 AFR AF: 0.0219

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0411

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.0184

Alfa AF: 0.0197 Hom.: 11

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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