rs749261367

Variant names:

• chr11-108325389-A-C
• rs749261367
• NM_000051.4:c.6652A>C

Your query was ambiguous. Multiple possible variants found:

• chr11-108325389-A-C
• chr11-108325389-A-G
• chr11-108325389-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP3

The NM_000051.4(ATM):​c.6652A>C​(p.Ser2218Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign 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. S2218N) has been classified as Likely benign. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 0.159
• Publications: 5 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

Specifications for ATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 43 uncertain in NM_000051.4
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.6652A>C	p.Ser2218Arg	missense	Exon 46 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6652A>C	p.Ser2218Arg	missense	Exon 47 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-16318T>G		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.6652A>C	p.Ser2218Arg	missense	Exon 46 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.6652A>C	p.Ser2218Arg	missense	Exon 47 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*1716A>C		non_coding_transcript_exon	Exon 44 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251178 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461624 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727100

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111884

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Familial cancer of breast (2)
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	Ataxia-telangiectasia syndrome (1)
-	1	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.40
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.16
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.096
Sift	Benign	0.22	T
Sift4G	Benign	0.36	T
Polyphen		0.0040	B
Vest4		0.16
MutPred		0.64		Gain of catalytic residue at S2218 (P = 0.0376)
MVP		0.76
MPC		0.14
ClinPred		0.21	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.086
gMVP		0.25
Mutation Taster		=85/15	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.67		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs749261367; hg19: chr11-108196116;