rs1295515377

chr11-108284448-A-Gchr11-108284448-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000051.4(ATM):c.3968A>G(p.Lys1323Arg) 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. 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. K1323E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.71

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32740086).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.3968A>G	p.Lys1323Arg	missense_variant	26/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.3968A>G	p.Lys1323Arg	missense_variant	26/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2017

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. 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, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ATM-related disease. This sequence change replaces lysine with arginine at codon 1323 of the ATM protein (p.Lys1323Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.0019	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T;D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	0.76	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.059	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.77	.;P;P
Vest4		0.55, 0.54
MutPred		0.23		Loss of ubiquitination at K1323 (P = 0.0039);Loss of ubiquitination at K1323 (P = 0.0039);Loss of ubiquitination at K1323 (P = 0.0039);
MVP		0.86
MPC		0.22
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.11
gMVP		0.26

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: rs1295515377; hg19: chr11-108155175;