Genetic Variant ATR:c.7656-705A>G (chr3-142453938-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001184.4(ATR):c.7656-705A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 152,078 control chromosomes in the GnomAD database, including 30,328 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.62 ( 30328 hom., cov: 32)

Consequence

ATR
NM_001184.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.254

Publications

7 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: Illumina, G2P, Ambry Genetics
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome
Inheritance: Unknown, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, 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:

ENSG00000295506 (HGNC:):

ENSG00000295506 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.78 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4 link	c.7656-705A>G		intron_variant	Intron 45 of 46	ENST00000350721.9	NP_001175.2	Q13535-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9 link	c.7656-705A>G		intron_variant	Intron 45 of 46	1	NM_001184.4	ENSP00000343741.4		Q13535-1

Frequencies

GnomAD3 genomes

AF:

0.621

AC:

94428

AN:

151958

Hom.:

30284

Cov.:

show subpopulations

Gnomad AFR

AF:

0.787

Gnomad AMI

AF:

0.701

Gnomad AMR

AF:

0.527

Gnomad ASJ

AF:

0.559

Gnomad EAS

AF:

0.469

Gnomad SAS

AF:

0.443

Gnomad FIN

AF:

0.544

Gnomad MID

AF:

0.619

Gnomad NFE

AF:

0.581

Gnomad OTH

AF:

0.613

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.622

AC:

94517

AN:

152078

Hom.:

30328

Cov.:

AF XY:

0.614

AC XY:

45634

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.787

AC:

32652

AN:

41492

American (AMR)

AF:

0.526

AC:

8029

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.559

AC:

1939

AN:

3466

East Asian (EAS)

AF:

0.469

AC:

2422

AN:

5164

South Asian (SAS)

AF:

0.442

AC:

2134

AN:

4826

European-Finnish (FIN)

AF:

0.544

AC:

5749

AN:

10576

Middle Eastern (MID)

AF:

0.606

AC:

177

AN:

292

European-Non Finnish (NFE)

AF:

0.581

AC:

39478

AN:

67974

Other (OTH)

AF:

0.617

AC:

1302

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1751

3502

5252

7003

8754

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

764

1528

2292

3056

3820

<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:

0.600

Hom.:

5239

Bravo

AF:

0.628

Asia WGS

AF:

0.505

AC:

1754

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.34

(source)

DANN

Benign

0.41

PhyloP100

-0.25

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over