Genetic Variant NM_001184.4:c.3120G>A (chr3-142549530-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001184.4(ATR):c.3120G>A(p.Leu1040Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,609,962 control chromosomes in the GnomAD database, including 392 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 ( 363 hom. )

Consequence

ATR
NM_001184.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.33

Publications

10 publications found

Variant links:

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BP6

Variant 3-142549530-C-T is Benign according to our data. Variant chr3-142549530-C-T is described in ClinVar as Benign. ClinVar VariationId is 157975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.33 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.018 (2735/152022) while in subpopulation SAS AF = 0.0413 (199/4816). AF 95% confidence interval is 0.0366. There are 29 homozygotes in GnomAd4. There are 1286 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.3120G>A	p.Leu1040Leu	synonymous	Exon 15 of 47	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.2928G>A	p.Leu976Leu	synonymous	Exon 14 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.3120G>A	p.Leu1040Leu	synonymous	Exon 15 of 47	ENSP00000343741.4	Q13535-1
ATR	ENST00000936442.1		c.2967G>A	p.Leu989Leu	synonymous	Exon 14 of 46	ENSP00000606501.1
ATR	ENST00000661310.1		c.2928G>A	p.Leu976Leu	synonymous	Exon 14 of 46	ENSP00000499589.1	Q13535-2

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

2734

AN:

151904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0417

Gnomad FIN

AF:

0.00284

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0185

Gnomad OTH

AF:

0.0187

GnomAD2 exomes

AF:

0.0176

AC:

4377

AN:

248354

AF XY:

0.0191

show subpopulations

Gnomad AFR exome

AF:

0.0178

Gnomad AMR exome

AF:

0.0109

Gnomad ASJ exome

AF:

0.0292

Gnomad EAS exome

AF:

0.000164

Gnomad FIN exome

AF:

0.00352

Gnomad NFE exome

AF:

0.0177

Gnomad OTH exome

AF:

0.0186

GnomAD4 exome

AF:

0.0196

AC:

28611

AN:

1457940

Hom.:

363

Cov.:

AF XY:

0.0202

AC XY:

14648

AN XY:

725234

show subpopulations

African (AFR)

AF:

0.0200

AC:

668

AN:

33384

American (AMR)

AF:

0.0112

AC:

497

AN:

44490

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

796

AN:

26072

East Asian (EAS)

AF:

0.000152

AC:

AN:

39600

South Asian (SAS)

AF:

0.0407

AC:

3481

AN:

85510

European-Finnish (FIN)

AF:

0.00371

AC:

198

AN:

53332

Middle Eastern (MID)

AF:

0.0377

AC:

213

AN:

5650

European-Non Finnish (NFE)

AF:

0.0193

AC:

21400

AN:

1109664

Other (OTH)

AF:

0.0224

AC:

1352

AN:

60238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

1271

2542

3814

5085

6356

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.0180

AC:

2735

AN:

152022

Hom.:

Cov.:

AF XY:

0.0173

AC XY:

1286

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0217

AC:

899

AN:

41474

American (AMR)

AF:

0.0127

AC:

194

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0326

AC:

113

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0413

AC:

199

AN:

4816

European-Finnish (FIN)

AF:

0.00284

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0185

AC:

1255

AN:

67950

Other (OTH)

AF:

0.0185

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

136

273

409

546

682

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0154

Hom.:

Bravo

AF:

0.0179

Asia WGS

AF:

0.0280

AC:

AN:

3478

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

-0.37

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

2.3

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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