rs28897763

chr3-142566145-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_001184.4(ATR):c.268C>T(p.His90Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00605 in 1,614,130 control chromosomes in the GnomAD database, including 142 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H90H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0077 (19 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (123 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.01

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 -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ATR
• BP4: Computational evidence support a benign effect (MetaRNN=0.00195992).
• BP6: Variant 3-142566145-G-A is Benign according to our data. Variant chr3-142566145-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 235760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142566145-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 19 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATR	NM_001184.4	c.268C>T	p.His90Tyr	missense_variant	3/47	ENST00000350721.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATR	ENST00000350721.9	c.268C>T	p.His90Tyr	missense_variant	3/47	1	NM_001184.4	P1

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1165 AN: 152154 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0639

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00642

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00847 AC: 2130 AN: 251486 Hom.: 56 AF XY: 0.00821 AC XY: 1116 AN XY: 135918

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0595

Gnomad NFE exome AF: 0.00670

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00588 AC: 8601 AN: 1461858 Hom.: 123 Cov.: 31 AF XY: 0.00585 AC XY: 4251 AN XY: 727238

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0549

Gnomad4 NFE exome AF: 0.00480

Gnomad4 OTH exome AF: 0.00417

GnomAD4 genome AF: 0.00765 AC: 1165 AN: 152272 Hom.: 19 Cov.: 31 AF XY: 0.00994 AC XY: 740 AN XY: 74438

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0639

Gnomad4 NFE AF: 0.00642

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00492 Hom.: 2

Bravo AF: 0.00277

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00757 AC: 919

EpiCase AF: 0.00622

EpiControl AF: 0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ATR: BP4, 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	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 23, 2015	- -
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	GeneDx	Feb 06, 2020	This variant is associated with the following publications: (PMID: 17010193) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Seckel syndrome 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 05, 2016

- -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.12
Sift	Benign	0.10	T
Sift4G	Benign	0.066	T
Polyphen		0.031	B
Vest4		0.28
MVP		0.41
MPC		0.20
ClinPred		0.0069	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.079
gMVP		0.063

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28897763; hg19: chr3-142284987; COSMIC: COSV63387997; COSMIC: COSV63387997;