Genetic Variant ATR:p.Tyr1956* (chr3-142496391-G-T) – ACMG Classification: Pathogenic (11 pts)

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP3

The NM_001184.4(ATR):c.5868C>A(p.Tyr1956*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000283 in 1,413,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y1956Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ATR
NM_001184.4 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.817

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4 link	c.5868C>A	p.Tyr1956*	stop_gained	Exon 34 of 47	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9 link	c.5868C>A	p.Tyr1956*	stop_gained	Exon 34 of 47	1	NM_001184.4	ENSP00000343741.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1413026

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

702952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32284

American (AMR)

AF:

0.00

AC:

AN:

43520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24614

East Asian (EAS)

AF:

0.00

AC:

AN:

38126

South Asian (SAS)

AF:

0.00

AC:

AN:

83142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51246

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5410

European-Non Finnish (NFE)

AF:

0.00000371

AC:

AN:

1077034

Other (OTH)

AF:

0.00

AC:

AN:

57650

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.048

FATHMM_MKL

Uncertain

0.85

PhyloP100

0.82

Vest4

0.95

GERP RS

-0.73

Mutation Taster

=2/198

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.75

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.75

Position offset: 4

DS_DL_spliceai

0.51

Position offset: -30

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