rs772591447

chr11-108227830-C-Achr11-108227830-C-Gchr11-108227830-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000051.4(ATM):c.127C>A(p.Leu43Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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. L43V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 0.728

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2187343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.127C>A	p.Leu43Ile	missense_variant	3/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.127C>A	p.Leu43Ile	missense_variant	3/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

This sequence change replaces leucine with isoleucine at codon 43 of the ATM protein (p.Leu43Ile). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and isoleucine. 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: "Probably 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2019

The p.L43I variant (also known as c.127C>A), located in coding exon 2 of the ATM gene, results from a C to A substitution at nucleotide position 127. The leucine at codon 43 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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. -

Ataxia-telangiectasia syndrome;C0006142:Malignant tumor of breast Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 09-01-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	0.069
Eigen_PC	Benign	-0.049
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;T;T;T;T;.;.;.;.;.;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.38	T
MutationTaster	Benign	0.56	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;N;N;N;.;N;.;.;.;.;.
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D;D;D;D;.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.;.;.;D;D
Polyphen		1.0, 1.0	.;D;.;.;.;D;D;D;D;D;.
Vest4		0.52, 0.69, 0.50, 0.72
MutPred		0.14		Gain of methylation at K41 (P = 0.0559);Gain of methylation at K41 (P = 0.0559);Gain of methylation at K41 (P = 0.0559);Gain of methylation at K41 (P = 0.0559);Gain of methylation at K41 (P = 0.0559);Gain of methylation at K41 (P = 0.0559);Gain of methylation at K41 (P = 0.0559);Gain of methylation at K41 (P = 0.0559);Gain of methylation at K41 (P = 0.0559);Gain of methylation at K41 (P = 0.0559);Gain of methylation at K41 (P = 0.0559);
MVP		0.77
MPC		0.61
ClinPred		0.95	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.28

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: rs772591447; hg19: chr11-108098557;