rs28367453

chr3-142561264-C-Gchr3-142561264-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001184.4(ATR):c.1328G>C(p.Arg443Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00082 in 1,613,910 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R443K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (6 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.978

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.

• PP2: Missense variant where missense usually causes diseases, ATR
• BP4: Computational evidence support a benign effect (MetaRNN=0.0033431053).
• BP6: Variant 3-142561264-C-G is Benign according to our data. Variant chr3-142561264-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 157963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142561264-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00408 (621/152176) while in subpopulation AFR AF= 0.0138 (573/41502). AF 95% confidence interval is 0.0129. There are 3 homozygotes in gnomad4. There are 298 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATR	NM_001184.4	c.1328G>C	p.Arg443Thr	missense_variant	5/47	ENST00000350721.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATR	ENST00000350721.9	c.1328G>C	p.Arg443Thr	missense_variant	5/47	1	NM_001184.4	P1

Frequencies

GnomAD3 genomes AF: 0.00408 AC: 621 AN: 152058 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00106 AC: 266 AN: 251456 Hom.: 1 AF XY: 0.000758 AC XY: 103 AN XY: 135900

Gnomad AFR exome AF: 0.0147

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000481 AC: 703 AN: 1461734 Hom.: 6 Cov.: 31 AF XY: 0.000385 AC XY: 280 AN XY: 727164

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00408 AC: 621 AN: 152176 Hom.: 3 Cov.: 32 AF XY: 0.00401 AC XY: 298 AN XY: 74404

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.000662 Hom.: 1

Bravo AF: 0.00468

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00123 AC: 150

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2022	See Variant Classification Assertion Criteria. -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome Benign:2

Likely 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

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 02, 2013

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	13
Dann	Benign	0.87
DEOGEN2	Benign	0.059	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.76	T;.
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.025
Sift	Uncertain	0.0090	D;T
Sift4G	Benign	0.16	T;.
Polyphen		0.090	B;.
Vest4		0.17
MVP		0.34
MPC		0.24
ClinPred		0.0040	T
GERP RS		1.6
Varity_R		0.084
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs28367453; hg19: chr3-142280106;