rs755656958

Variant names:

• chr11-108325350-T-C
• rs755656958
• NM_000051.4:c.6613T>C

Your query was ambiguous. Multiple possible variants found:

• chr11-108325350-T-C
• chr11-108325350-T-G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000051.4(ATM):​c.6613T>C​(p.Trp2205Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,398 control chromosomes in the GnomAD database, including 1 homozygotes. 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. W2205C) has been classified as Uncertain significance. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.000013 (1 hom., cov: 30)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.30
• 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]

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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

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.6613T>C	p.Trp2205Arg	missense	Exon 46 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6613T>C	p.Trp2205Arg	missense	Exon 47 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-16279A>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.6613T>C	p.Trp2205Arg	missense	Exon 46 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.6613T>C	p.Trp2205Arg	missense	Exon 47 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*1677T>C		non_coding_transcript_exon	Exon 44 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151280 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151398 Hom.: 1 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 73954

African (AFR) AF: 0.00 AC: 0 AN: 41242

American (AMR) AF: 0.00 AC: 0 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2102

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	Ataxia-telangiectasia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.88		Gain of disorder (P = 0.0021)
MVP		0.99
MPC		0.78
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.84
Mutation Taster		=6/94	disease causing

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: rs755656958; hg19: chr11-108196077;