rs11916455

Variant names:

• chr3-142503232-C-T
• rs11916455
• NM_001184.4:c.5288+130G>A

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.5288+130G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 632,804 control chromosomes in the GnomAD database, including 44,149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9410 hom., cov: 32)
  • Exomes 𝑓: 0.37 (34739 hom.)
• Consequence: ATR NM_001184.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.961
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-142503232-C-T is Benign according to our data. Variant chr3-142503232-C-T is described in ClinVar as Benign. ClinVar VariationId is 678204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.408 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.5288+130G>A		intron	N/A	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.5096+130G>A		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.5288+130G>A		intron	N/A	ENSP00000343741.4	Q13535-1
	ATR	ENST00000936442.1		c.5135+130G>A		intron	N/A	ENSP00000606501.1
	ATR	ENST00000661310.1		c.5096+130G>A		intron	N/A	ENSP00000499589.1	Q13535-2

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51940 AN: 151892 Hom.: 9406 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.580

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.354

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.383

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.370

GnomAD4 exome AF: 0.371 AC: 178374 AN: 480794 Hom.: 34739 AF XY: 0.368 AC XY: 93847 AN XY: 255316

African (AFR) AF: 0.192 AC: 2331 AN: 12142

American (AMR) AF: 0.316 AC: 5336 AN: 16890

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 6065 AN: 13450

East Asian (EAS) AF: 0.312 AC: 8824 AN: 28320

South Asian (SAS) AF: 0.244 AC: 9514 AN: 39010

European-Finnish (FIN) AF: 0.378 AC: 15652 AN: 41418

Middle Eastern (MID) AF: 0.393 AC: 764 AN: 1946

European-Non Finnish (NFE) AF: 0.398 AC: 120505 AN: 302432

Other (OTH) AF: 0.373 AC: 9383 AN: 25186

GnomAD4 genome AF: 0.342 AC: 51962 AN: 152010 Hom.: 9410 Cov.: 32 AF XY: 0.342 AC XY: 25400 AN XY: 74328

African (AFR) AF: 0.203 AC: 8406 AN: 41456

American (AMR) AF: 0.354 AC: 5411 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1559 AN: 3468

East Asian (EAS) AF: 0.354 AC: 1833 AN: 5172

South Asian (SAS) AF: 0.272 AC: 1310 AN: 4820

European-Finnish (FIN) AF: 0.383 AC: 4038 AN: 10554

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27967 AN: 67938

Other (OTH) AF: 0.372 AC: 785 AN: 2108

Alfa AF: 0.369 Hom.: 1435

Bravo AF: 0.337

Asia WGS AF: 0.323 AC: 1122 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	7.3
DANN	Benign	0.55
PhyloP100		-0.96
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: rs11916455; hg19: chr3-142222074; COSMIC: COSV107452148; COSMIC: COSV107452148;