rs77208665

chr3-142555928-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_001184.4(ATR):c.2290A>G(p.Lys764Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00459 in 1,612,994 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K764K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (30 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 4.14

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATR
• BP4: Computational evidence support a benign effect (MetaRNN=0.009344518).
• BP6: Variant 3-142555928-T-C is Benign according to our data. Variant chr3-142555928-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 157970.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=2, Uncertain_significance=1}. Variant chr3-142555928-T-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATR	NM_001184.4	c.2290A>G	p.Lys764Glu	missense_variant	10/47	ENST00000350721.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATR	ENST00000350721.9	c.2290A>G	p.Lys764Glu	missense_variant	10/47	1	NM_001184.4	P1

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00507

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00329 AC: 823 AN: 250116 Hom.: 5 AF XY: 0.00317 AC XY: 428 AN XY: 135104

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00253

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000864

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00498

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00472 AC: 6889 AN: 1460704 Hom.: 30 Cov.: 31 AF XY: 0.00445 AC XY: 3233 AN XY: 726554

Gnomad4 AFR exome AF: 0.000599

Gnomad4 AMR exome AF: 0.00234

Gnomad4 ASJ exome AF: 0.00670

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000769

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.00542

Gnomad4 OTH exome AF: 0.00618

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74466

Gnomad4 AFR AF: 0.000674

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00507

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00459 Hom.: 4

Bravo AF: 0.00351

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00325 AC: 395

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00567

EpiControl AF: 0.00551

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATR p.Lys764Glu variant was identified in 1 of 100 proband chromosomes (frequency: 0.01) from individuals or families with breast cancer and was not identified in 72 control chromosomes from healthy individuals (Durocher_2006_17010193). In Wang et al., the variant was also identified in 1/48 breast cancer tumours (Wang_2008_PMID: 18281469). The variant was also identified in the following databases: dbSNP (ID: rs77208665) and was found in ClinVar (where it was reported as likely benign and a VUS for Seckel syndrome 1), Clinvitae, Cosmic (with a FATHMM prediction of Pathogenic (score=0.95)), MutDB and LOVD 3.0. The variant was identified in control databases in 902 of 281492 chromosomes (5 homozygous) at a frequency of 0.003204 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 64 of 10326 chromosomes (freq: 0.006198), European (non-Finnish) in 630 of 128766 chromosomes (freq: 0.004893), other in 26 of 7180 chromosomes (freq: 0.003621), Latino in 89 of 35200 chromosomes (freq: 0.002528), European (Finnish) in 53 of 25088 chromosomes (freq: 0.002113), South Asian in 26 of 30084 chromosomes (freq: 0.000864) and African in 14 of 24956 chromosomes (freq: 0.000561); it was not observed in the East Asian populations. The p.Lys764 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 20, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ATR: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2019	This variant is associated with the following publications: (PMID: 28787443) -

Seckel syndrome 1 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 14, 2013	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.031
Eigen_PC	Benign	0.0053
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.21
Sift	Benign	0.042	D
Sift4G	Uncertain	0.021	D
Polyphen		0.92	P
Vest4		0.62
MVP		0.79
MPC		0.53
ClinPred		0.011	T
GERP RS		4.2
Varity_R		0.36
gMVP		0.34

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: rs77208665; hg19: chr3-142274770; COSMIC: COSV63389180; COSMIC: COSV63389180;