rs779145081

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3

The NM_000051.4(ATM):ā€‹c.8246A>Gā€‹(p.Lys2749Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,612,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K2749I) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000075 ( 0 hom. )

Consequence

ATM
NM_000051.4 missense

Scores

6
7
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 8.80
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]
C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000051.4
PP3
MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATMNM_000051.4 linkuse as main transcriptc.8246A>G p.Lys2749Arg missense_variant 56/63 ENST00000675843.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATMENST00000675843.1 linkuse as main transcriptc.8246A>G p.Lys2749Arg missense_variant 56/63 NM_000051.4 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152168
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1459896
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
726408
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000991
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152168
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 09, 2022This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 2749 of the ATM protein (p.Lys2749Arg). This variant is present in population databases (rs779145081, gnomAD 0.0008%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 407546). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ATM protein function. 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
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 02, 2023Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 23532176, 30287823) -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 13, 2023The p.K2749R variant (also known as c.8246A>G), located in coding exon 55 of the ATM gene, results from an A to G substitution at nucleotide position 8246. The lysine at codon 2749 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
24
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.12
T;T
Eigen
Uncertain
0.68
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.87
D;.
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.78
D;D
MetaSVM
Uncertain
0.59
D
MutationAssessor
Benign
1.3
L;L
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-2.2
N;N
REVEL
Uncertain
0.59
Sift
Pathogenic
0.0
D;D
Sift4G
Benign
0.084
T;T
Polyphen
0.99
D;D
Vest4
0.76
MutPred
0.47
Loss of methylation at K2749 (P = 6e-04);Loss of methylation at K2749 (P = 6e-04);
MVP
0.97
MPC
0.51
ClinPred
0.96
D
GERP RS
5.6
Varity_R
0.41
gMVP
0.46

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.

Other links and lift over

dbSNP: rs779145081; hg19: chr11-108206666; API