3-142549530-C-T

Variant names:

• chr3-142549530-C-T
• rs28910272
• NM_001184.4:c.3120G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001184.4(ATR):​c.3120G>A​(p.Leu1040Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,609,962 control chromosomes in the GnomAD database, including 392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (29 hom., cov: 32)
  • Exomes 𝑓: 0.020 (363 hom.)
• Consequence: ATR NM_001184.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.33

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 3-142549530-C-T is Benign according to our data. Variant chr3-142549530-C-T is described in ClinVar as [Benign]. Clinvar id is 157975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142549530-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.33 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.018 (2735/152022) while in subpopulation SAS AF= 0.0413 (199/4816). AF 95% confidence interval is 0.0366. There are 29 homozygotes in gnomad4. There are 1286 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4	c.3120G>A	p.Leu1040Leu	synonymous_variant	Exon 15 of 47	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.3120G>A	p.Leu1040Leu	synonymous_variant	Exon 15 of 47	1	NM_001184.4	ENSP00000343741.4

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2734 AN: 151904 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0326

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0417

Gnomad FIN AF: 0.00284

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0187

GnomAD3 exomes AF: 0.0176 AC: 4377 AN: 248354 Hom.: 74 AF XY: 0.0191 AC XY: 2571 AN XY: 134686

Gnomad AFR exome AF: 0.0178

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.0292

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0415

Gnomad FIN exome AF: 0.00352

Gnomad NFE exome AF: 0.0177

Gnomad OTH exome AF: 0.0186

GnomAD4 exome AF: 0.0196 AC: 28611 AN: 1457940 Hom.: 363 Cov.: 31 AF XY: 0.0202 AC XY: 14648 AN XY: 725234

Gnomad4 AFR exome AF: 0.0200

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0305

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0407

Gnomad4 FIN exome AF: 0.00371

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0224

GnomAD4 genome AF: 0.0180 AC: 2735 AN: 152022 Hom.: 29 Cov.: 32 AF XY: 0.0173 AC XY: 1286 AN XY: 74308

Gnomad4 AFR AF: 0.0217

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.0326

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0413

Gnomad4 FIN AF: 0.00284

Gnomad4 NFE AF: 0.0185

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0153 Hom.: 3

Bravo AF: 0.0179

Asia WGS AF: 0.0280 AC: 97 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Apr 28, 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 variant of interest causes a synonymous change involving a conserved nucleotide with 4/5 in silico programs via Alamut predicting an effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2205/111476 (1/50 including 40 homozygotes), which exceeds the predicted maximum expected allele frequency for a pathogenic ATR variant of 1/1666666. In addition, a reputable clinical laboratory cites the variant as "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

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

- -

Mar 03, 2015

GeneDx

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

- -

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

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. -

Feb 08, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 02, 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	-0.37
CADD	Benign	15
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs28910272; hg19: chr3-142268372; COSMIC: COSV63385660;