11-108256215-A-T

Variant names:

• chr11-108256215-A-T
• rs864622259
• NM_000051.4:c.2125A>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000051.4(ATM):​c.2125A>T​(p.Ile709Phe) variant causes a missense, splice region 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. 17/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I709I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 0.001463
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0420

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06558269).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.2125A>T	p.Ile709Phe	missense_variant, splice_region_variant	Exon 14 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2125A>T	p.Ile709Phe	missense_variant, splice_region_variant	Exon 14 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 245775). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 709 of the ATM protein (p.Ile709Phe). -

not provided Uncertain:1

Feb 24, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted ATM c.2125A>T at the cDNA level, p.Ile709Phe (I709F) at the protein level, and results in the change of an Isoleucine to a Phenylalanine (ATT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ile709Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. ATM Ile709Phe occurs at a position that is not conserved and is not located in a known functional domain (Tavtigian 2009, UniProt). While protein-based in silico analyses predict that this variant is unlikely to alter protein structure or function, multiple splicing models predict that this variant may damage the natural splice acceptor site for intron 13 and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether ATM Ile709Phe is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I709F variant (also known as c.2125A>T), located in coding exon 13 of the ATM gene, results from an A to T substitution at nucleotide position 2125. This variant impacts the first base pair of coding exon 13. The isoleucine at codon 709 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is poorly 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	0.085
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.13	.;T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.73	T;T;.
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.066	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	.;L;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.055	.;B;B
Vest4		0.18, 0.22
MutPred		0.096		Loss of stability (P = 0.127);Loss of stability (P = 0.127);Loss of stability (P = 0.127);
MVP		0.87
MPC		0.22
ClinPred		0.093	T
GERP RS		0.54
Varity_R		0.085
gMVP		0.094

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.14
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs864622259; hg19: chr11-108126942;