rs2227932

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001184.4(ATR):c.5460T>C(p.Tyr1820=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,613,800 control chromosomes in the GnomAD database, including 10,072 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.079 ( 672 hom., cov: 31)

Exomes 𝑓: 0.11 ( 9400 hom. )

Consequence

ATR
NM_001184.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.50

Variant links:

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]

ATR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 3-142498695-A-G is Benign according to our data. Variant chr3-142498695-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142498695-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.5 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATR	NM_001184.4 linkuse as main transcript	c.5460T>C	p.Tyr1820=	synonymous_variant	32/47	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9 linkuse as main transcript	c.5460T>C	p.Tyr1820=	synonymous_variant	32/47	1	NM_001184.4	ENSP00000343741	P1	Q13535-1

Frequencies

GnomAD3 genomes

AF:

0.0787

AC:

11966

AN:

152132

Hom.:

669

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0198

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0582

Gnomad ASJ

AF:

0.0812

Gnomad EAS

AF:

0.00308

Gnomad SAS

AF:

0.154

Gnomad FIN

AF:

0.133

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.0736

GnomAD3 exomes

AF:

0.0922

AC:

23126

AN:

250950

Hom.:

1357

AF XY:

0.0992

AC XY:

13454

AN XY:

135638

show subpopulations

Gnomad AFR exome

AF:

0.0161

Gnomad AMR exome

AF:

0.0401

Gnomad ASJ exome

AF:

0.0794

Gnomad EAS exome

AF:

0.00136

Gnomad SAS exome

AF:

0.161

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.110

Gnomad OTH exome

AF:

0.0872

GnomAD4 exome

AF:

0.108

AC:

157739

AN:

1461550

Hom.:

9400

Cov.:

AF XY:

0.110

AC XY:

79853

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.0152

Gnomad4 AMR exome

AF:

0.0432

Gnomad4 ASJ exome

AF:

0.0804

Gnomad4 EAS exome

AF:

0.000806

Gnomad4 SAS exome

AF:

0.159

Gnomad4 FIN exome

AF:

0.128

Gnomad4 NFE exome

AF:

0.114

Gnomad4 OTH exome

AF:

0.0980

GnomAD4 genome

AF:

0.0786

AC:

11972

AN:

152250

Hom.:

672

Cov.:

AF XY:

0.0782

AC XY:

5825

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0197

Gnomad4 AMR

AF:

0.0582

Gnomad4 ASJ

AF:

0.0812

Gnomad4 EAS

AF:

0.00308

Gnomad4 SAS

AF:

0.155

Gnomad4 FIN

AF:

0.133

Gnomad4 NFE

AF:

0.112

Gnomad4 OTH

AF:

0.0724

Alfa

AF:

0.0986

Hom.:

771

Bravo

AF:

0.0669

Asia WGS

AF:

0.0670

AC:

233

AN:

3478

EpiCase

AF:

0.0993

EpiControl

AF:

0.103

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 25, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 18, 2013	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

Seckel syndrome 1

Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

9.1

DANN

Benign

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over