rs35962982

Variant names:

• chr11-108293469-C-G
• rs35962982
• NM_000051.4:c.4768C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-108293469-C-G
• chr11-108293469-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000051.4(ATM):​c.4768C>G​(p.Leu1590Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. L1590F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.11
• Publications: 0 publications found

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]

ATM Gene-Disease associations (from GenCC):

• ATM-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 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, 30 uncertain in NM_000051.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.4768C>G	p.Leu1590Val	missense	Exon 31 of 63	NP_000042.3
	ATM	NM_001351834.2		c.4768C>G	p.Leu1590Val	missense	Exon 32 of 64	NP_001338763.1	Q13315

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.4768C>G	p.Leu1590Val	missense	Exon 31 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.4768C>G	p.Leu1590Val	missense	Exon 32 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000531525.3	TSL:1	c.4437-1458C>G		intron	N/A	ENSP00000434327.3	H0YDU7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458398 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725734

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.00 AC: 0 AN: 86130

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5664

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109518

Other (OTH) AF: 0.00 AC: 0 AN: 60242

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Ataxia-telangiectasia syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.058	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.32		Loss of helix (P = 0.1299)
MVP		0.93
MPC		0.58
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.50
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs35962982; hg19: chr11-108164196;