rs376676328

Variant names:

• chr11-108353828-A-G
• rs376676328
• NM_000051.4:c.8734A>G

Your query was ambiguous. Multiple possible variants found:

• chr11-108353828-A-G
• chr11-108353828-A-T

Variant summary

Our verdict is Uncertain significance. The variant received -3 ACMG points: 1P and 4B. BP2_Strong PP3

This summary comes from the ClinGen Evidence Repository: The ATM c.8734A>G (p.Arg2912Gly) variant is predicted deleterious by multiple protein in silico tools (PP3). This variant has been observed in a compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, GTR Lab IDs: 61756, 500031, <-4.0 POINTS). In summary, this variant meets criteria to be classified as uncertain significance based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157198/MONDO:0016419/020

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:27 B:3 O:2
• Conservation: PhyloP100: 3.98
• Publications: 33 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 -3 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BP2: For more information check the summary or visit ClinGen Evidence Repository.

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.8734A>G	p.Arg2912Gly	missense	Exon 60 of 63	NP_000042.3
	ATM	NM_001351834.2		c.8734A>G	p.Arg2912Gly	missense	Exon 61 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.640+32092T>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.8734A>G	p.Arg2912Gly	missense	Exon 60 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.8734A>G	p.Arg2912Gly	missense	Exon 61 of 64	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*1196+1087T>C		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000219 AC: 55 AN: 251450 AF XY: 0.000235

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000413

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000183 AC: 267 AN: 1461760 Hom.: 1 Cov.: 31 AF XY: 0.000198 AC XY: 144 AN XY: 727180

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 9 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000210 AC: 233 AN: 1111908

Other (OTH) AF: 0.000232 AC: 14 AN: 60392

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74464

African (AFR) AF: 0.0000241 AC: 1 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000367 AC: 25 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000187 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000491

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	7	-	not provided (7)
-	5	1	Hereditary cancer-predisposing syndrome (6)
-	5	-	Ataxia-telangiectasia syndrome (5)
-	3	1	Familial cancer of breast (4)
-	3	-	not specified (4)
-	1	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (2)
-	1	-	ATM-related cancer predisposition (1)
-	1	-	ATM-related disorder (1)
-	1	-	Breast and/or ovarian cancer (1)
-	-	1	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.96
MPC		0.66
ClinPred		0.78	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.92
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs376676328; hg19: chr11-108224555;