rs730881324

Variant names:

• chr11-108343358-A-G
• rs730881324
• NM_000051.4:c.8405A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000051.4(ATM):​c.8405A>G​(p.Gln2802Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000185 in 1,461,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q2802Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 4.67
• Publications: 1 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]

C11orf65 (HGNC:28519): (chromosome 11 open reading frame 65) Predicted to be involved in negative regulation of mitochondrial fission and negative regulation of protein targeting to mitochondrion. Predicted to be located in cytosol and mitochondrial outer membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 42 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.13847986).

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.8405A>G	p.Gln2802Arg	missense	Exon 57 of 63	NP_000042.3
	ATM	NM_001351834.2		c.8405A>G	p.Gln2802Arg	missense	Exon 58 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-34287T>C		intron	N/A	NP_001317297.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.8405A>G	p.Gln2802Arg	missense	Exon 57 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.8405A>G	p.Gln2802Arg	missense	Exon 58 of 64	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*1197-8066T>C		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251168 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461628 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727118

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000671 AC: 3 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111848

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	2	-	Ataxia-telangiectasia syndrome (2)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-1.7	N
PhyloP100		4.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.28
Sift	Benign	0.93	T
Sift4G	Benign	1.0	T
Polyphen		0.029	B
Vest4		0.26
MutPred		0.57		Gain of MoRF binding (P = 0.0166)
MVP		0.73
MPC		0.13
ClinPred		0.097	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.63
Mutation Taster		=65/35	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: rs730881324; hg19: chr11-108214085;