rs2229033

chr3-142562511-C-Gchr3-142562511-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.891G>C(p.Lys297Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,613,860 control chromosomes in the GnomAD database, including 151 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 (★★). Synonymous variant affecting the same amino acid position (i.e. K297K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0098 (5 hom., cov: 33)
  • Exomes 𝑓: 0.013 (146 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.117

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=0.008547455).
• BP6: Variant 3-142562511-C-G is Benign according to our data. Variant chr3-142562511-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 158005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142562511-C-G is described in Lovd as [Benign]. Variant chr3-142562511-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00984 (1499/152278) while in subpopulation NFE AF= 0.0161 (1092/68010). AF 95% confidence interval is 0.0153. There are 5 homozygotes in gnomad4. There are 705 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATR	NM_001184.4	c.891G>C	p.Lys297Asn	missense_variant	4/47	ENST00000350721.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATR	ENST00000350721.9	c.891G>C	p.Lys297Asn	missense_variant	4/47	1	NM_001184.4	P1

Frequencies

GnomAD3 genomes AF: 0.00986 AC: 1501 AN: 152160 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0161

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.0101 AC: 2547 AN: 251084 Hom.: 24 AF XY: 0.0100 AC XY: 1357 AN XY: 135744

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.00579

Gnomad ASJ exome AF: 0.0181

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0125 AC: 18296 AN: 1461582 Hom.: 146 Cov.: 30 AF XY: 0.0123 AC XY: 8968 AN XY: 727090

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.00564

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00231

Gnomad4 FIN exome AF: 0.0129

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.0119

GnomAD4 genome AF: 0.00984 AC: 1499 AN: 152278 Hom.: 5 Cov.: 33 AF XY: 0.00947 AC XY: 705 AN XY: 74458

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000827

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.0161

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.0136 Hom.: 14

Bravo AF: 0.00860

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0164 AC: 141

ExAC AF: 0.0104 AC: 1269

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0144

EpiControl AF: 0.0148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ATR: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 02, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2017	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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Vantari Genetics

Oct 23, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	15
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.64	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.097
Sift	Benign	0.15	T
Sift4G	Benign	0.12	T
Polyphen		0.20	B
Vest4		0.19
MutPred		0.18		Loss of ubiquitination at K297 (P = 0.021);
MPC		0.21
ClinPred		0.0097	T
GERP RS		3.5
Varity_R		0.15
gMVP		0.31

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: rs2229033; hg19: chr3-142281353; COSMIC: COSV63384505; COSMIC: COSV63384505;