11-108293319-G-T

Position:

• chr11-108293319-G-T

Variant summary

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

The NM_000051.4(ATM):​c.4618G>T​(p.Asp1540Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,383,310 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.945

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.4618G>T	p.Asp1540Tyr	missense_variant	31/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4618G>T	p.Asp1540Tyr	missense_variant	31/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000130 AC: 3 AN: 230222 Hom.: 0 AF XY: 0.0000241 AC XY: 3 AN XY: 124610

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: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000506 AC: 7 AN: 1383310 Hom.: 0 Cov.: 27 AF XY: 0.00000870 AC XY: 6 AN XY: 689414

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: 0.0000878

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 28, 2021	This sequence change replaces aspartic acid with tyrosine at codon 1540 of the ATM protein (p.Asp1540Tyr). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs778622948, ExAC 0.008%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The p.D1540Y variant (also known as c.4618G>T), located in coding exon 30 of the ATM gene, results from a G to T substitution at nucleotide position 4618. The aspartic acid at codon 1540 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.91	D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.80	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.26
Sift	Benign	0.030	D;D
Sift4G	Benign	0.082	T;T
Polyphen		0.96	D;D
Vest4		0.61
MutPred		0.40		Gain of methylation at K1536 (P = 0.0994);Gain of methylation at K1536 (P = 0.0994);
MVP		0.79
MPC		0.35
ClinPred		0.91	D
GERP RS		4.4
Varity_R		0.18
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs778622948; hg19: chr11-108164046;