rs587779842

chr11-108243954-A-Cchr11-108243954-A-Gchr11-108243954-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000051.4(ATM):c.498A>C(p.Glu166Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E166G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002556
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.109

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 4 ACMG points.

• PM1: In a helix (size 15) in uniprot entity ATM_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108235834-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 627570.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.17875826).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.498A>C	p.Glu166Asp	missense_variant, splice_region_variant	6/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.498A>C	p.Glu166Asp	missense_variant, splice_region_variant	6/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1400704 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 692680

Gnomad4 AFR exome AF: 0.0000322

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2013

This variant, in exon 6 of the ATM gene, is denoted c.498A>C at the cDNA level and p.Glu166Asp (E166D) at the protein level. This amino acid substitution results in the conservative replacement of an uncharged Glutamic Acid residue (GAA) with an uncharged Aspartic Acid residue (GAC) at a position that is conserved throughout evolution. ATM Glu166Asp variant is not located within a known functional domain. In silico analyses predict this variant to have a benign effect on protein structure and function. ATM Glu166Asp has not been published in the literature as a mutation nor has it been reported as a benign polymorphism, to our knowledge. The NHLBI ESP Exome Variant Server reports ATM Glu166Asp was not observed in approximately 6,500 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Therefore, there is not enough information currently available to determine whether ATM Glu166Asp is a pathogenic mutation or a rare benign variant. The variant is found in HEREDICANCER panel(s). -

Ataxia-telangiectasia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 08, 2021

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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 127396). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with aspartic acid at codon 166 of the ATM protein (p.Glu166Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	14
Dann	Benign	0.96
Eigen	Benign	0.13
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.60	T;T;.
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.17	N;N;N
REVEL	Benign	0.091
Sift	Benign	0.50	T;T;T
Sift4G	Benign	0.79	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.17, 0.13
MutPred		0.30		Gain of relative solvent accessibility (P = 0.2363);Gain of relative solvent accessibility (P = 0.2363);Gain of relative solvent accessibility (P = 0.2363);
MVP		0.94
MPC		0.11
ClinPred		0.20	T
GERP RS		3.1
Varity_R		0.15
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.032
SpliceAI score (max)		0.030		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: rs587779842; hg19: chr11-108114681;