3-142459302-C-T

Variant names:

• chr3-142459302-C-T
• rs2229032
• NM_001184.4:c.7274G>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.7274G>A​(p.Arg2425Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,772 control chromosomes in the GnomAD database, including 18,203 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2425L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.13 (1344 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16859 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0370
• Publications: 70 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001532197).
• BP6: Variant 3-142459302-C-T is Benign according to our data. Variant chr3-142459302-C-T is described in ClinVar as Benign. ClinVar VariationId is 136470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 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.7274G>A	p.Arg2425Gln	missense	Exon 43 of 47	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.7082G>A	p.Arg2361Gln	missense	Exon 42 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.7274G>A	p.Arg2425Gln	missense	Exon 43 of 47	ENSP00000343741.4	Q13535-1
	ATR	ENST00000513291.2	TSL:1	n.2458G>A		non_coding_transcript_exon	Exon 13 of 16
	ATR	ENST00000936442.1		c.7121G>A	p.Arg2374Gln	missense	Exon 42 of 46	ENSP00000606501.1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19374 AN: 152002 Hom.: 1340 Cov.: 32

Gnomad AFR AF: 0.0810

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0845

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0982

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.135

GnomAD2 exomes AF: 0.131 AC: 32811 AN: 251230 AF XY: 0.131

Gnomad AFR exome AF: 0.0795

Gnomad AMR exome AF: 0.0994

Gnomad ASJ exome AF: 0.0798

Gnomad EAS exome AF: 0.0982

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.149 AC: 217372 AN: 1461652 Hom.: 16859 Cov.: 34 AF XY: 0.147 AC XY: 106950 AN XY: 727134

African (AFR) AF: 0.0736 AC: 2465 AN: 33474

American (AMR) AF: 0.101 AC: 4513 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0794 AC: 2074 AN: 26126

East Asian (EAS) AF: 0.114 AC: 4541 AN: 39678

South Asian (SAS) AF: 0.100 AC: 8636 AN: 86246

European-Finnish (FIN) AF: 0.167 AC: 8918 AN: 53412

Middle Eastern (MID) AF: 0.105 AC: 608 AN: 5768

European-Non Finnish (NFE) AF: 0.159 AC: 177307 AN: 1111846

Other (OTH) AF: 0.138 AC: 8310 AN: 60384

GnomAD4 genome AF: 0.127 AC: 19375 AN: 152120 Hom.: 1344 Cov.: 32 AF XY: 0.125 AC XY: 9319 AN XY: 74358

African (AFR) AF: 0.0808 AC: 3356 AN: 41532

American (AMR) AF: 0.110 AC: 1675 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0845 AC: 293 AN: 3468

East Asian (EAS) AF: 0.101 AC: 522 AN: 5160

South Asian (SAS) AF: 0.0989 AC: 477 AN: 4824

European-Finnish (FIN) AF: 0.163 AC: 1727 AN: 10580

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10888 AN: 67962

Other (OTH) AF: 0.137 AC: 289 AN: 2112

Alfa AF: 0.144 Hom.: 6024

Bravo AF: 0.120

TwinsUK AF: 0.161 AC: 597

ALSPAC AF: 0.147 AC: 568

ESP6500AA AF: 0.0881 AC: 388

ESP6500EA AF: 0.158 AC: 1357

ExAC AF: 0.133 AC: 16083

Asia WGS AF: 0.0990 AC: 347 AN: 3478

EpiCase AF: 0.155

EpiControl AF: 0.150

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (2)
-	-	2	Seckel syndrome 1 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.68
DANN	Benign	0.84
DEOGEN2	Benign	0.053	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.61	N
PhyloP100		0.037
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.17
Sift	Benign	0.56	T
Sift4G	Benign	0.44	T
Polyphen		0.0	B
Vest4		0.022
MPC		0.72
ClinPred		0.0046	T
GERP RS		-9.1
Varity_R		0.046
gMVP		0.072
Mutation Taster		=99/1	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: rs2229032; hg19: chr3-142178144; COSMIC: COSV63383988; COSMIC: COSV63383988;