11-108365423-G-T

Variant names:

• chr11-108365423-G-T
• rs201199629
• NM_000051.4:c.9086G>T

Variant summary

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

The NM_000051.4(ATM):​c.9086G>T​(p.Gly3029Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.45

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]

ACMG classification

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	c.9086G>T	p.Gly3029Val	missense_variant	Exon 63 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.9086G>T	p.Gly3029Val	missense_variant	Exon 63 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251462 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ataxia-telangiectasia syndrome Uncertain:1

Feb 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3029 of the ATM protein (p.Gly3029Val). This variant is present in population databases (rs201199629, gnomAD 0.0009%). 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: 421788). 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 disruptive. 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 25, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted ATM c.9086G>T at the cDNA level, p.Gly3029Val (G3029V) at the protein level, and results in the change of a Glycine to a Valine (GGT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Gly3029Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. ATM Gly3029Val occurs at a position that is not conserved and is located in FATC domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Gly3029Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;.
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.52
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.85	P;P
Vest4		0.51
MutPred		0.57		Loss of disorder (P = 0.1113);Loss of disorder (P = 0.1113);
MVP		0.89
MPC		0.40
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.56
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

Other links and lift over

dbSNP: rs201199629; hg19: chr11-108236150;