rs868748140

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000051.4(ATM):c.268A>G(p.Arg90Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R90S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.04

Variant links:

Genes affected

ATM (HGNC:795): (ATM serine/threonine kinase) The protein encoded by this gene belongs to the PI3/PI4-kinase family. This protein is an important cell cycle checkpoint kinase that phosphorylates; thus, it functions as a regulator of a wide variety of downstream proteins, including tumor suppressor proteins p53 and BRCA1, checkpoint kinase CHK2, checkpoint proteins RAD17 and RAD9, and DNA repair protein NBS1. This protein and the closely related kinase ATR are thought to be master controllers of cell cycle checkpoint signaling pathways that are required for cell response to DNA damage and for genome stability. Mutations in this gene are associated with ataxia telangiectasia, an autosomal recessive disorder. [provided by RefSeq, Aug 2010]

ATM links:

Y_RNA (HGNC:):

Y_RNA links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4 link	c.268A>G	p.Arg90Gly	missense_variant	Exon 4 of 63	ENST00000675843.1	NP_000042.3	Q13315A0A024R3C7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1 link	c.268A>G	p.Arg90Gly	missense_variant	Exon 4 of 63		NM_000051.4	ENSP00000501606.1		Q13315

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461534

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Nov 27, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R90G variant (also known as c.268A>G), located in coding exon 3 of the ATM gene, results from an A to G substitution at nucleotide position 268. The arginine at codon 90 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Dec 31, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome

Uncertain:1

Aug 28, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with glycine at codon 90 of the ATM protein (p.Arg90Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

not provided

Uncertain:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ATM: PM2, BP1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

.;T;T;T;.;T;T;T;T;T;T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D;D;D;D;.;.;.;.;.;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.53

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.47

MutationAssessor

Uncertain

2.4

.;M;.;.;.;M;.;.;.;.;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.6

D;N;D;D;.;N;.;.;.;.;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0070

D;D;D;D;.;D;.;.;.;.;.

Sift4G

Uncertain

0.0060

D;D;T;D;T;D;.;.;.;T;T

Polyphen

0.92, 0.99

.;P;.;.;.;P;D;D;D;D;.

Vest4

0.88, 0.86, 0.70, 0.82

MutPred

0.32

Gain of ubiquitination at K93 (P = 0.0232);Gain of ubiquitination at K93 (P = 0.0232);Gain of ubiquitination at K93 (P = 0.0232);Gain of ubiquitination at K93 (P = 0.0232);Gain of ubiquitination at K93 (P = 0.0232);Gain of ubiquitination at K93 (P = 0.0232);Gain of ubiquitination at K93 (P = 0.0232);Gain of ubiquitination at K93 (P = 0.0232);Gain of ubiquitination at K93 (P = 0.0232);Gain of ubiquitination at K93 (P = 0.0232);Gain of ubiquitination at K93 (P = 0.0232);

MVP

0.86

MPC

0.56

ClinPred

0.99

GERP RS

4.9

Varity_R

0.64

gMVP

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over