rs112018640

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001184.4(ATR):c.5868C>T(p.Tyr1956=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00964 in 1,549,054 control chromosomes in the GnomAD database, including 289 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 21 hom., cov: 28)

Exomes 𝑓: 0.0096 ( 268 hom. )

Consequence

ATR
NM_001184.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.817

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.44).

BP6

Variant 3-142496391-G-A is Benign according to our data. Variant chr3-142496391-G-A is described in ClinVar as [Benign]. Clinvar id is 157996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142496391-G-A is described in Lovd as [Likely_benign]. Variant chr3-142496391-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.817 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0105 (1433/136252) while in subpopulation SAS AF= 0.0246 (102/4140). AF 95% confidence interval is 0.0208. There are 21 homozygotes in gnomad4. There are 665 alleles in male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATR	NM_001184.4 linkuse as main transcript	c.5868C>T	p.Tyr1956=	synonymous_variant	34/47	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.5868C>T	p.Tyr1956=	synonymous_variant	34/47	1	NM_001184.4	ENSP00000343741	P1	Q13535-1

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1433

AN:

136164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0115

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00708

Gnomad ASJ

AF:

0.0201

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0251

Gnomad FIN

AF:

0.000770

Gnomad MID

AF:

0.00769

Gnomad NFE

AF:

0.0113

Gnomad OTH

AF:

0.00980

GnomAD3 exomes

AF:

0.00920

AC:

2268

AN:

246470

Hom.:

AF XY:

0.0102

AC XY:

1358

AN XY:

133100

show subpopulations

Gnomad AFR exome

AF:

0.00719

Gnomad AMR exome

AF:

0.00576

Gnomad ASJ exome

AF:

0.0126

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0238

Gnomad FIN exome

AF:

0.00199

Gnomad NFE exome

AF:

0.00927

Gnomad OTH exome

AF:

0.00933

GnomAD4 exome

AF:

0.00956

AC:

13505

AN:

1412802

Hom.:

268

Cov.:

AF XY:

0.0101

AC XY:

7105

AN XY:

702812

show subpopulations

Gnomad4 AFR exome

AF:

0.00784

Gnomad4 AMR exome

AF:

0.00575

Gnomad4 ASJ exome

AF:

0.0137

Gnomad4 EAS exome

AF:

0.0000525

Gnomad4 SAS exome

AF:

0.0243

Gnomad4 FIN exome

AF:

0.00193

Gnomad4 NFE exome

AF:

0.00914

Gnomad4 OTH exome

AF:

0.0103

GnomAD4 genome

AF:

0.0105

AC:

1433

AN:

136252

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

665

AN XY:

65312

show subpopulations

Gnomad4 AFR

AF:

0.0115

Gnomad4 AMR

AF:

0.00707

Gnomad4 ASJ

AF:

0.0201

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0246

Gnomad4 FIN

AF:

0.000770

Gnomad4 NFE

AF:

0.0113

Gnomad4 OTH

AF:

0.00971

Alfa

AF:

0.0160

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 05, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 02, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

-0.44

CADD

Benign

DANN

Benign

0.39

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