3-142512266-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001184.4(ATR):c.4846T>C(p.Ser1616Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000076 in 1,579,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1616A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

ATR
NM_001184.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.392

Publications

4 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04755038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4 link	c.4846T>C	p.Ser1616Pro	missense_variant	Exon 27 of 47	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.4846T>C	p.Ser1616Pro	missense_variant	Exon 27 of 47	1	NM_001184.4	ENSP00000343741.4		Q13535-1

Frequencies

GnomAD3 genomes

AF:

0.00000670

AC:

AN:

149288

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251050

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000769

AC:

AN:

1429902

Hom.:

Cov.:

AF XY:

0.00000982

AC XY:

AN XY:

712764

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32476

American (AMR)

AF:

0.00

AC:

AN:

44424

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25564

East Asian (EAS)

AF:

0.00

AC:

AN:

39020

South Asian (SAS)

AF:

0.00

AC:

AN:

85746

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.0000101

AC:

AN:

1085970

Other (OTH)

AF:

0.00

AC:

AN:

58810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

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

AF:

0.00000670

AC:

AN:

149288

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72686

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40662

American (AMR)

AF:

0.00

AC:

AN:

15018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5098

South Asian (SAS)

AF:

0.00

AC:

AN:

4742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67524

Other (OTH)

AF:

0.00

AC:

AN:

2050

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.S1616P variant (also known as c.4846T>C), located in coding exon 27 of the ATR gene, results from a T to C substitution at nucleotide position 4846. The serine at codon 1616 is replaced by proline, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 835654). This variant has not been reported in the literature in individuals affected with ATR-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1616 of the ATR protein (p.Ser1616Pro). -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome

Uncertain:1

Feb 08, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Seckel syndrome 1

Uncertain:1

Feb 08, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.7

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.085

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.48

M_CAP

Benign

0.0073

MetaRNN

Benign

0.048

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

PhyloP100

0.39

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.1

REVEL

Benign

0.017

Sift

Benign

0.13

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.12

MutPred

0.40

Gain of methylation at K1613 (P = 0.0531);

MVP

0.12

MPC

0.79

ClinPred

0.038

GERP RS

-2.2

Varity_R

0.18

gMVP

0.25

Mutation Taster

=93/7

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over