chr3-142449489-C-T

Variant names:

• chr3-142449489-C-T
• rs1802904
• NM_001184.4:c.7875G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001184.4(ATR):​c.7875G>A​(p.Gln2625Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.871 in 1,613,102 control chromosomes in the GnomAD database, including 612,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (60127 hom., cov: 32)
  • Exomes 𝑓: 0.87 (552567 hom.)
• Consequence: ATR NM_001184.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.24
• Publications: 44 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

ENSG00000295506 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 3-142449489-C-T is Benign according to our data. Variant chr3-142449489-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.962 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.7875G>A	p.Gln2625Gln	synonymous	Exon 47 of 47	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.7683G>A	p.Gln2561Gln	synonymous	Exon 46 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.7875G>A	p.Gln2625Gln	synonymous	Exon 47 of 47	ENSP00000343741.4	Q13535-1
	ATR	ENST00000513291.2	TSL:1	n.6584G>A		non_coding_transcript_exon	Exon 16 of 16
	ATR	ENST00000936442.1		c.7722G>A	p.Gln2574Gln	synonymous	Exon 46 of 46	ENSP00000606501.1

Frequencies

GnomAD3 genomes AF: 0.887 AC: 134880 AN: 152128 Hom.: 60074 Cov.: 32

Gnomad AFR AF: 0.970

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.807

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.929

Gnomad SAS AF: 0.938

Gnomad FIN AF: 0.804

Gnomad MID AF: 0.845

Gnomad NFE AF: 0.866

Gnomad OTH AF: 0.872

GnomAD2 exomes AF: 0.858 AC: 215739 AN: 251404 AF XY: 0.863

Gnomad AFR exome AF: 0.973

Gnomad AMR exome AF: 0.756

Gnomad ASJ exome AF: 0.777

Gnomad EAS exome AF: 0.933

Gnomad FIN exome AF: 0.811

Gnomad NFE exome AF: 0.856

Gnomad OTH exome AF: 0.843

GnomAD4 exome AF: 0.869 AC: 1269266 AN: 1460856 Hom.: 552567 Cov.: 52 AF XY: 0.871 AC XY: 632790 AN XY: 726804

African (AFR) AF: 0.974 AC: 32586 AN: 33462

American (AMR) AF: 0.765 AC: 34217 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 20239 AN: 26118

East Asian (EAS) AF: 0.908 AC: 36011 AN: 39676

South Asian (SAS) AF: 0.935 AC: 80661 AN: 86234

European-Finnish (FIN) AF: 0.810 AC: 43281 AN: 53420

Middle Eastern (MID) AF: 0.861 AC: 4964 AN: 5766

European-Non Finnish (NFE) AF: 0.868 AC: 964425 AN: 1111102

Other (OTH) AF: 0.876 AC: 52882 AN: 60360

GnomAD4 genome AF: 0.887 AC: 134988 AN: 152246 Hom.: 60127 Cov.: 32 AF XY: 0.883 AC XY: 65740 AN XY: 74428

African (AFR) AF: 0.970 AC: 40307 AN: 41570

American (AMR) AF: 0.806 AC: 12320 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2721 AN: 3472

East Asian (EAS) AF: 0.929 AC: 4810 AN: 5178

South Asian (SAS) AF: 0.939 AC: 4540 AN: 4834

European-Finnish (FIN) AF: 0.804 AC: 8511 AN: 10582

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.866 AC: 58922 AN: 68002

Other (OTH) AF: 0.874 AC: 1847 AN: 2114

Alfa AF: 0.866 Hom.: 112869

Bravo AF: 0.887

Asia WGS AF: 0.937 AC: 3256 AN: 3478

EpiCase AF: 0.863

EpiControl AF: 0.858

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Seckel syndrome 1 (2)
-	-	1	Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	3.3
DANN	Benign	0.79
PhyloP100		1.2
Mutation Taster		=60/40	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: rs1802904; hg19: chr3-142168331; COSMIC: COSV99377126; COSMIC: COSV99377126;