rs1555096955

chr11-108289062-A-Gchr11-108289062-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000051.4(ATM):c.4195A>G(p.Thr1399Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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. T1399S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.81

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 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12298447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.4195A>G	p.Thr1399Ala	missense_variant	28/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.4195A>G	p.Thr1399Ala	missense_variant	28/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 04, 2023	This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1399 of the ATM protein (p.Thr1399Ala). This variant has not been reported in the literature in individuals affected with ATM-related conditions. 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 478925). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 03, 2019

The p.T1399A variant (also known as c.4195A>G), located in coding exon 27 of the ATM gene, results from an A to G substitution at nucleotide position 4195. The threonine at codon 1399 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	22
Dann	Benign	0.96
DEOGEN2	Benign	0.084	T;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.0061
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.69	T;.;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	0.88	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.1	N;N;.
REVEL	Benign	0.065
Sift	Benign	0.29	T;T;.
Sift4G	Benign	0.59	T;T;T
Polyphen		0.013	B;B;.
Vest4		0.052
MVP		0.81
MPC		0.13
ClinPred		0.51	D
GERP RS		4.2
Varity_R		0.10
gMVP		0.16

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: rs1555096955; hg19: chr11-108159789;