rs9869842

Variant names:

• chr3-142553472-G-A
• rs9869842
• NM_001184.4:c.2634-74C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001184.4(ATR):​c.2634-74C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,502,864 control chromosomes in the GnomAD database, including 253,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30711 hom., cov: 31)
  • Exomes 𝑓: 0.57 (223274 hom.)
• Consequence: ATR NM_001184.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.79
• Publications: 13 publications found

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 Gene-Disease associations (from GenCC):

• Seckel syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome

  Inheritance: Unknown, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• Seckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• familial prostate carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 3-142553472-G-A is Benign according to our data. Variant chr3-142553472-G-A is described in ClinVar as Benign. ClinVar VariationId is 670440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.786 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4	c.2634-74C>T		intron_variant	Intron 12 of 46	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.2634-74C>T		intron_variant	Intron 12 of 46	1	NM_001184.4	ENSP00000343741.4

Frequencies

GnomAD3 genomes AF: 0.627 AC: 94929 AN: 151498 Hom.: 30660 Cov.: 31

Gnomad AFR AF: 0.793

Gnomad AMI AF: 0.679

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.445

Gnomad FIN AF: 0.541

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.621

GnomAD4 exome AF: 0.572 AC: 772814 AN: 1351248 Hom.: 223274 Cov.: 24 AF XY: 0.568 AC XY: 384269 AN XY: 676562

African (AFR) AF: 0.800 AC: 23974 AN: 29952

American (AMR) AF: 0.468 AC: 20076 AN: 42862

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 14296 AN: 25372

East Asian (EAS) AF: 0.444 AC: 16948 AN: 38174

South Asian (SAS) AF: 0.436 AC: 35914 AN: 82404

European-Finnish (FIN) AF: 0.550 AC: 26844 AN: 48840

Middle Eastern (MID) AF: 0.565 AC: 3130 AN: 5544

European-Non Finnish (NFE) AF: 0.586 AC: 599014 AN: 1021364

Other (OTH) AF: 0.575 AC: 32618 AN: 56736

GnomAD4 genome AF: 0.627 AC: 95027 AN: 151616 Hom.: 30711 Cov.: 31 AF XY: 0.619 AC XY: 45855 AN XY: 74086

African (AFR) AF: 0.793 AC: 32767 AN: 41296

American (AMR) AF: 0.534 AC: 8152 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1945 AN: 3468

East Asian (EAS) AF: 0.468 AC: 2398 AN: 5128

South Asian (SAS) AF: 0.445 AC: 2133 AN: 4798

European-Finnish (FIN) AF: 0.541 AC: 5668 AN: 10474

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.587 AC: 39853 AN: 67890

Other (OTH) AF: 0.626 AC: 1315 AN: 2102

Alfa AF: 0.624 Hom.: 4584

Bravo AF: 0.633

Asia WGS AF: 0.506 AC: 1760 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.081
DANN	Benign	0.14
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9869842; hg19: chr3-142272314; COSMIC: COSV63385113; COSMIC: COSV63385113;