rs9867946

Variant names:

• chr3-142519150-T-G
• rs9867946
• NM_001184.4:c.4382+519A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001184.4(ATR):​c.4382+519A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0665 in 152,188 control chromosomes in the GnomAD database, including 1,087 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.067 (1087 hom., cov: 32)
• Consequence: ATR NM_001184.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.200
• Publications: 1 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: G2P, Ambry Genetics, Illumina
• familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome

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

  Inheritance: AD Classification: MODERATE Submitted by: 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATR	NM_001184.4	MANE Select	c.4382+519A>C		intron	N/A	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.4190+519A>C		intron	N/A	NP_001341508.1	Q13535-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATR	ENST00000350721.9	TSL:1 MANE Select	c.4382+519A>C		intron	N/A	ENSP00000343741.4	Q13535-1
	ATR	ENST00000936442.1		c.4229+519A>C		intron	N/A	ENSP00000606501.1
	ATR	ENST00000661310.1		c.4190+519A>C		intron	N/A	ENSP00000499589.1	Q13535-2

Frequencies

GnomAD3 genomes AF: 0.0663 AC: 10089 AN: 152070 Hom.: 1079 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00885

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.0466

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

GnomAD4 genome AF: 0.0665 AC: 10127 AN: 152188 Hom.: 1087 Cov.: 32 AF XY: 0.0645 AC XY: 4798 AN XY: 74420

African (AFR) AF: 0.225 AC: 9339 AN: 41498

American (AMR) AF: 0.0273 AC: 417 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00868 AC: 45 AN: 5186

South Asian (SAS) AF: 0.0295 AC: 142 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68004

Other (OTH) AF: 0.0466 AC: 98 AN: 2104

Alfa AF: 0.0235 Hom.: 780

Bravo AF: 0.0737

Asia WGS AF: 0.0350 AC: 120 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.4
DANN	Benign	0.66
PhyloP100		0.20
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: rs9867946; hg19: chr3-142237992;