NM_001184.4:c.4846T>C

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

19

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

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
ATRNM_001184.4 linkc.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
ATRENST00000350721.9 linkc.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:
1
AN:
149288
Hom.:
0
Cov.:
32
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:
1
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:
11
AN:
1429902
Hom.:
0
Cov.:
35
AF XY:
0.00000982
AC XY:
7
AN XY:
712764
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32476
American (AMR)
AF:
0.00
AC:
0
AN:
44424
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25564
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39020
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85746
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52364
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5528
European-Non Finnish (NFE)
AF:
0.0000101
AC:
11
AN:
1085970
Other (OTH)
AF:
0.00
AC:
0
AN:
58810
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.448
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
1
AN:
149288
Hom.:
0
Cov.:
32
AF XY:
0.0000138
AC XY:
1
AN XY:
72686
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
40662
American (AMR)
AF:
0.00
AC:
0
AN:
15018
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3450
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5098
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4742
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
9534
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
308
European-Non Finnish (NFE)
AF:
0.0000148
AC:
1
AN:
67524
Other (OTH)
AF:
0.00
AC:
0
AN:
2050
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
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
T
BayesDel_noAF
Benign
-0.76
CADD
Benign
6.7
DANN
Benign
0.93
DEOGEN2
Benign
0.085
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.028
N
LIST_S2
Benign
0.48
T
M_CAP
Benign
0.0073
T
MetaRNN
Benign
0.048
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.0
N
PhyloP100
0.39
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-1.1
N
REVEL
Benign
0.017
Sift
Benign
0.13
T
Sift4G
Benign
0.30
T
Polyphen
0.0
B
Vest4
0.12
MutPred
0.40
Gain of methylation at K1613 (P = 0.0531);
MVP
0.12
MPC
0.79
ClinPred
0.038
T
GERP RS
-2.2
Varity_R
0.18
gMVP
0.25
Mutation Taster
=93/7
polymorphism

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

Other links and lift over

dbSNP: rs201492267; hg19: chr3-142231108; API