3-142503114-A-G

Variant names:

• chr3-142503114-A-G
• rs9856772
• NM_001184.4:c.5288+248T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001184.4(ATR):​c.5288+248T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.923 in 152,248 control chromosomes in the GnomAD database, including 65,034 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.92 (65034 hom., cov: 30)
• Consequence: ATR NM_001184.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0390
• Publications: 8 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 3-142503114-A-G is Benign according to our data. Variant chr3-142503114-A-G is described in ClinVar as Benign. ClinVar VariationId is 678106.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4	c.5288+248T>C		intron_variant	Intron 30 of 46	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.5288+248T>C		intron_variant	Intron 30 of 46	1	NM_001184.4	ENSP00000343741.4

Frequencies

GnomAD3 genomes AF: 0.923 AC: 140434 AN: 152130 Hom.: 64974 Cov.: 30

Gnomad AFR AF: 0.977

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.934

Gnomad ASJ AF: 0.829

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.975

Gnomad FIN AF: 0.837

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.897

Gnomad OTH AF: 0.916

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.923 AC: 140554 AN: 152248 Hom.: 65034 Cov.: 30 AF XY: 0.922 AC XY: 68634 AN XY: 74418

African (AFR) AF: 0.977 AC: 40606 AN: 41546

American (AMR) AF: 0.934 AC: 14298 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.829 AC: 2876 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5182 AN: 5182

South Asian (SAS) AF: 0.975 AC: 4698 AN: 4818

European-Finnish (FIN) AF: 0.837 AC: 8866 AN: 10590

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.897 AC: 61043 AN: 68022

Other (OTH) AF: 0.917 AC: 1936 AN: 2112

Alfa AF: 0.896 Hom.: 25848

Bravo AF: 0.930

Asia WGS AF: 0.985 AC: 3425 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.4
DANN	Benign	0.78
PhyloP100		-0.039
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: rs9856772; hg19: chr3-142221956;