3-142515692-G-A

Variant names:

• chr3-142515692-G-A
• rs10804682
• NM_001184.4:c.4383-177C>T

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.4383-177C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 151,976 control chromosomes in the GnomAD database, including 2,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.15 (2008 hom., cov: 31)
• Consequence: ATR NM_001184.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.664
• Publications: 17 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=-0.85).
• BP6: Variant 3-142515692-G-A is Benign according to our data. Variant chr3-142515692-G-A is described in ClinVar as Benign. ClinVar VariationId is 678203.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4	c.4383-177C>T		intron_variant	Intron 24 of 46	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.4383-177C>T		intron_variant	Intron 24 of 46	1	NM_001184.4	ENSP00000343741.4
ATR	ENST00000661310.1	c.4191-177C>T		intron_variant	Intron 23 of 45			ENSP00000499589.1
ATR	ENST00000653868.1	n.4412-177C>T		intron_variant	Intron 24 of 34
ATR	ENST00000656590.1	n.3171-177C>T		intron_variant	Intron 20 of 43			ENSP00000499225.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22343 AN: 151858 Hom.: 2012 Cov.: 31

Gnomad AFR AF: 0.0492

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.211

Gnomad EAS AF: 0.0784

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.207

Gnomad OTH AF: 0.176

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

GnomAD4 genome AF: 0.147 AC: 22342 AN: 151976 Hom.: 2008 Cov.: 31 AF XY: 0.145 AC XY: 10740 AN XY: 74290

African (AFR) AF: 0.0493 AC: 2043 AN: 41482

American (AMR) AF: 0.134 AC: 2052 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 732 AN: 3468

East Asian (EAS) AF: 0.0783 AC: 406 AN: 5182

South Asian (SAS) AF: 0.108 AC: 519 AN: 4802

European-Finnish (FIN) AF: 0.156 AC: 1647 AN: 10552

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.207 AC: 14076 AN: 67926

Other (OTH) AF: 0.174 AC: 366 AN: 2098

Alfa AF: 0.191 Hom.: 4627

Bravo AF: 0.141

Asia WGS AF: 0.105 AC: 362 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	-0.85
CADD	Benign	6.0
DANN	Benign	0.53
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10804682; hg19: chr3-142234534;