rs143806447

Positions:

• chr3-142503393-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BP4_Strong

The NM_001184.4(ATR):​c.5257A>G​(p.Ile1753Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00039 in 1,608,672 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (1 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 7.36

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATR. . Gene score misZ 4.3648 (greater than the threshold 3.09). Trascript score misZ 7.1274 (greater than threshold 3.09). GenCC has associacion of gene with sarcoma, Seckel syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Seckel syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.038006812).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATR	NM_001184.4	c.5257A>G	p.Ile1753Val	missense_variant	30/47	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.5257A>G	p.Ile1753Val	missense_variant	30/47	1	NM_001184.4	ENSP00000343741	P1

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000370 AC: 93 AN: 251020 Hom.: 0 AF XY: 0.000450 AC XY: 61 AN XY: 135672

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000423

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000406 AC: 592 AN: 1456486 Hom.: 1 Cov.: 29 AF XY: 0.000422 AC XY: 306 AN XY: 724936

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00113

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000419

Gnomad4 OTH exome AF: 0.000399

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74354

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.000280

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000428 AC: 52

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000383

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 25, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1753 of the ATR protein (p.Ile1753Val). This variant is present in population databases (rs143806447, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ATR-related conditions. ClinVar contains an entry for this variant (Variation ID: 434450). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Seckel syndrome 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 22, 2016

- -

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.069	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.15
Sift	Benign	0.10	T
Sift4G	Benign	0.14	T
Polyphen		0.93	P
Vest4		0.33
MVP		0.36
MPC		0.88
ClinPred		0.071	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs143806447; hg19: chr3-142222235; COSMIC: COSV63388199; COSMIC: COSV63388199;