11-108244788-A-T

Position:

• chr11-108244788-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000051.4(ATM):​c.663A>T​(p.Arg221Ser) 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R221G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001457
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37051946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.663A>T	p.Arg221Ser	missense_variant, splice_region_variant	7/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.663A>T	p.Arg221Ser	missense_variant, splice_region_variant	7/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2019

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 missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ATM-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 221 of the ATM protein (p.Arg221Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	.;T;T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;T;.
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.4	.;M;M
MutationTaster	Benign	0.96	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.5	D;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.034	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.72, 0.75
MutPred		0.39		Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);Gain of disorder (P = 0.0461);
MVP		0.94
MPC		0.40
ClinPred		0.97	D
GERP RS		-0.082
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.10
SpliceAI score (max)		0.13		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: rs1555066913; hg19: chr11-108115515;