11-108244898-T-G

Position:

• chr11-108244898-T-G

Variant summary

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

The NM_000051.4(ATM):​c.773T>G​(p.Ile258Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71

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]

ATM (HGNC:):

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/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.773T>G	p.Ile258Ser	missense_variant	7/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.773T>G	p.Ile258Ser	missense_variant	7/63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2014

This variant is denoted ATM c.773T>G at the cDNA level, p.Ile258Ser (I258S) at the protein level, and results in the change of an Isoleucine to a Serine (ATT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Ile258Ser 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 Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Ile258Ser occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Ile258Ser is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	.;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;.
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.8	.;L;L
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.20	T;T;T
Sift4G	Uncertain	0.0020	D;T;T
Polyphen		0.87	.;P;P
Vest4		0.85, 0.85
MutPred		0.44		Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);Loss of helix (P = 0.0167);
MVP		0.89
MPC		0.31
ClinPred		0.94	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.64

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: rs730881337; hg19: chr11-108115625;