3-142549530-C-T

Position:

chr3-142549530-C-T

Variant summary

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

The ENST00000350721.9(ATR):c.3120G>A(p.Leu1040=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,609,962 control chromosomes in the GnomAD database, including 392 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 29 hom., cov: 32)

Exomes 𝑓: 0.020 ( 363 hom. )

Consequence

ATR
ENST00000350721.9 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 2.33

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=-0.37).

BP6

Variant 3-142549530-C-T is Benign according to our data. Variant chr3-142549530-C-T is described in ClinVar as [Benign]. Clinvar id is 157975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-142549530-C-T is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=2.33 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.018 (2735/152022) while in subpopulation SAS AF= 0.0413 (199/4816). AF 95% confidence interval is 0.0366. There are 29 homozygotes in gnomad4. There are 1286 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATR	NM_001184.4 linkuse as main transcript	c.3120G>A	p.Leu1040=	synonymous_variant	15/47	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.3120G>A	p.Leu1040=	synonymous_variant	15/47	1	NM_001184.4	ENSP00000343741	P1	Q13535-1

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

2734

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0417

Gnomad FIN

AF:

0.00284

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.0187

GnomAD3 exomes

AF:

0.0176

AC:

4377

AN:

248354

Hom.:

AF XY:

0.0191

AC XY:

2571

AN XY:

134686

show subpopulations

Gnomad AFR exome

AF:

0.0178

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.0292

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.0415

Gnomad FIN exome

AF:

0.00352

Gnomad NFE exome

AF:

0.0177

Gnomad OTH exome

AF:

0.0186

GnomAD4 exome

AF:

0.0196

AC:

28611

AN:

1457940

Hom.:

363

Cov.:

AF XY:

0.0202

AC XY:

14648

AN XY:

725234

show subpopulations

Gnomad4 AFR exome

AF:

0.0200

Gnomad4 AMR exome

AF:

0.0112

Gnomad4 ASJ exome

AF:

0.0305

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.0407

Gnomad4 FIN exome

AF:

0.00371

Gnomad4 NFE exome

AF:

0.0193

Gnomad4 OTH exome

AF:

0.0224

GnomAD4 genome

AF:

0.0180

AC:

2735

AN:

152022

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1286

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0217

Gnomad4 AMR

AF:

0.0127

Gnomad4 ASJ

AF:

0.0326

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0413

Gnomad4 FIN

AF:

0.00284

Gnomad4 NFE

AF:

0.0185

Gnomad4 OTH

AF:

0.0185

Alfa

AF:

0.0153

Hom.:

Bravo

AF:

0.0179

Asia WGS

AF:

0.0280

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 02, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 28, 2016	Variant summary: The variant of interest causes a synonymous change involving a conserved nucleotide with 4/5 in silico programs via Alamut predicting an effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2205/111476 (1/50 including 40 homozygotes), which exceeds the predicted maximum expected allele frequency for a pathogenic ATR variant of 1/1666666. In addition, a reputable clinical laboratory cites the variant as "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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 12, 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	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 02, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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