NM_000051.4:c.2603A>T

Variant names:

• chr11-108267307-A-T
• rs750322758
• NM_000051.4:c.2603A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000051.4(ATM):​c.2603A>T​(p.Asp868Val) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.70

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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25405264).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.2603A>T	p.Asp868Val	missense_variant	Exon 17 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.2603A>T	p.Asp868Val	missense_variant	Exon 17 of 63		NM_000051.4	ENSP00000501606.1

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

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 08, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D868V variant (also known as c.2603A>T), located in coding exon 16 of the ATM gene, results from an A to T substitution at nucleotide position 2603. The aspartic acid at codon 868 is replaced by valine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.093	.;T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.81	T;T;.
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.5	.;M;M
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.033	D;D;D
Sift4G	Uncertain	0.0030	D;T;T
Polyphen		0.059	.;B;B
Vest4		0.62, 0.64
MutPred		0.18		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.85
MPC		0.19
ClinPred		0.88	D
GERP RS		4.1
Varity_R		0.12
gMVP		0.35

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: rs750322758; hg19: chr11-108138034;