rs28897765

Variant names:

• chr3-142561266-T-C
• rs28897765
• NM_001184.4:c.1326A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001184.4(ATR):​c.1326A>G​(p.Lys442Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0197 in 1,613,898 control chromosomes in the GnomAD database, including 400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (30 hom., cov: 32)
  • Exomes 𝑓: 0.020 (370 hom.)
• Consequence: ATR NM_001184.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.327
• Publications: 14 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 3-142561266-T-C is Benign according to our data. Variant chr3-142561266-T-C is described in ClinVar as Benign. ClinVar VariationId is 157962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.327 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.018 (2744/152228) while in subpopulation SAS AF = 0.0411 (198/4822). AF 95% confidence interval is 0.0364. There are 30 homozygotes in GnomAd4. There are 1289 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AR,AD,Unknown gene

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.1326A>G	p.Lys442Lys	synonymous	Exon 5 of 47	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.1326A>G	p.Lys442Lys	synonymous	Exon 5 of 46	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.1326A>G	p.Lys442Lys	synonymous	Exon 5 of 47	ENSP00000343741.4	Q13535-1
	ATR	ENST00000936442.1		c.1326A>G	p.Lys442Lys	synonymous	Exon 5 of 46	ENSP00000606501.1
	ATR	ENST00000661310.1		c.1326A>G	p.Lys442Lys	synonymous	Exon 5 of 46	ENSP00000499589.1	Q13535-2

Frequencies

GnomAD3 genomes AF: 0.0180 AC: 2743 AN: 152110 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0414

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.0182 AC: 4584 AN: 251452 AF XY: 0.0197

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.0184

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0198 AC: 28998 AN: 1461670 Hom.: 370 Cov.: 31 AF XY: 0.0204 AC XY: 14851 AN XY: 727144

African (AFR) AF: 0.0209 AC: 698 AN: 33474

American (AMR) AF: 0.0114 AC: 509 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0307 AC: 802 AN: 26130

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39674

South Asian (SAS) AF: 0.0412 AC: 3553 AN: 86250

European-Finnish (FIN) AF: 0.00376 AC: 201 AN: 53418

Middle Eastern (MID) AF: 0.0378 AC: 218 AN: 5766

European-Non Finnish (NFE) AF: 0.0195 AC: 21640 AN: 1111850

Other (OTH) AF: 0.0227 AC: 1371 AN: 60386

GnomAD4 genome AF: 0.0180 AC: 2744 AN: 152228 Hom.: 30 Cov.: 32 AF XY: 0.0173 AC XY: 1289 AN XY: 74444

African (AFR) AF: 0.0219 AC: 910 AN: 41540

American (AMR) AF: 0.0127 AC: 194 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0411 AC: 198 AN: 4822

European-Finnish (FIN) AF: 0.00283 AC: 30 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0185 AC: 1255 AN: 67996

Other (OTH) AF: 0.0184 AC: 39 AN: 2114

Alfa AF: 0.0198 Hom.: 12

Bravo AF: 0.0181

Asia WGS AF: 0.0270 AC: 95 AN: 3478

EpiCase AF: 0.0224

EpiControl AF: 0.0200

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	2	Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (2)
-	-	2	Seckel syndrome 1 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.4
DANN	Benign	0.46
PhyloP100		0.33
Mutation Taster		=98/2	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: rs28897765; hg19: chr3-142280108; COSMIC: COSV63385670;