dbSNP rs28910270: ATR:p.Glu650Glu (chr3-142556511-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001184.4(ATR):c.1950G>A(p.Glu650Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,614,042 control chromosomes in the GnomAD database, including 399 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 29 hom., cov: 32)

Exomes 𝑓: 0.020 ( 370 hom. )

Consequence

ATR
NM_001184.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.32

Publications

14 publications found

Variant links:

COSMIC-nc: COSV63385666

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

ATR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 3-142556511-C-T is Benign according to our data. Variant chr3-142556511-C-T is described in ClinVar as Benign. ClinVar VariationId is 157968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.32 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0178 (2705/152282) while in subpopulation SAS AF = 0.0411 (198/4822). AF 95% confidence interval is 0.0364. There are 29 homozygotes in GnomAd4. There are 1271 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 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.1950G>A	p.Glu650Glu	synonymous	Exon 9 of 47	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.1758G>A	p.Glu586Glu	synonymous	Exon 8 of 46	NP_001341508.1	Q13535-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ATR	ENST00000350721.9	TSL:1 MANE Select	c.1950G>A	p.Glu650Glu	synonymous	Exon 9 of 47	ENSP00000343741.4	Q13535-1
ATR	ENST00000936442.1		c.1797G>A	p.Glu599Glu	synonymous	Exon 8 of 46	ENSP00000606501.1
ATR	ENST00000661310.1		c.1758G>A	p.Glu586Glu	synonymous	Exon 8 of 46	ENSP00000499589.1	Q13535-2

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2705

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0210

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0124

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0414

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0184

Gnomad OTH

AF:

0.0186

GnomAD2 exomes

AF:

0.0181

AC:

4557

AN:

251250

AF XY:

0.0196

show subpopulations

Gnomad AFR exome

AF:

0.0188

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:

0.0183

Gnomad OTH exome

AF:

0.0193

GnomAD4 exome

AF:

0.0198

AC:

28979

AN:

1461760

Hom.:

370

Cov.:

AF XY:

0.0204

AC XY:

14839

AN XY:

727180

show subpopulations

African (AFR)

AF:

0.0200

AC:

669

AN:

33478

American (AMR)

AF:

0.0113

AC:

507

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0307

AC:

802

AN:

26128

East Asian (EAS)

AF:

0.000151

AC:

AN:

39686

South Asian (SAS)

AF:

0.0412

AC:

3554

AN:

86248

European-Finnish (FIN)

AF:

0.00376

AC:

201

AN:

53410

Middle Eastern (MID)

AF:

0.0380

AC:

219

AN:

5768

European-Non Finnish (NFE)

AF:

0.0195

AC:

21652

AN:

1111942

Other (OTH)

AF:

0.0227

AC:

1369

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1544

3088

4633

6177

7721

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

860

1720

2580

3440

4300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0178

AC:

2705

AN:

152282

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1271

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0210

AC:

874

AN:

41554

American (AMR)

AF:

0.0124

AC:

190

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0326

AC:

113

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.0411

AC:

198

AN:

4822

European-Finnish (FIN)

AF:

0.00283

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0184

AC:

1255

AN:

68034

Other (OTH)

AF:

0.0184

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

139

279

418

558

697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0194

Hom.:

Bravo

AF:

0.0179

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0224

EpiControl

AF:

0.0200

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (2)

Seckel syndrome 1 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

3.9

(source)

DANN

Benign

0.42

PhyloP100

-1.3

Mutation Taster

=90/10

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over