rs529296539

Variant names:

• chr11-108345819-G-A
• rs529296539
• NM_000051.4:c.8495G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-108345819-G-A
• chr11-108345819-G-C
• chr11-108345819-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1 PM5 BS2

The NM_000051.4(ATM):​c.8495G>A​(p.Arg2832His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,613,710 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2832S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (2 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:17 B:1 O:1
• Conservation: PhyloP100: 9.98
• Publications: 24 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 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 38 uncertain in NM_000051.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-108345818-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3720488.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

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.8495G>A	p.Arg2832His	missense	Exon 58 of 63	NP_000042.3
	ATM	NM_001351834.2		c.8495G>A	p.Arg2832His	missense	Exon 59 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-36748C>T		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.8495G>A	p.Arg2832His	missense	Exon 58 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.8495G>A	p.Arg2832His	missense	Exon 59 of 64	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*1196+9096C>T		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000119 AC: 30 AN: 251276 AF XY: 0.000103

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000855 AC: 125 AN: 1461538 Hom.: 2 Cov.: 30 AF XY: 0.000100 AC XY: 73 AN XY: 727062

African (AFR) AF: 0.0000897 AC: 3 AN: 33460

American (AMR) AF: 0.0000224 AC: 1 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39648

South Asian (SAS) AF: 0.000707 AC: 61 AN: 86240

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53406

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111806

Other (OTH) AF: 0.0000662 AC: 4 AN: 60378

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74412

African (AFR) AF: 0.0000241 AC: 1 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67966

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

Alfa AF: 0.0000789 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	-	Ataxia-telangiectasia syndrome (5)
-	4	-	not provided (4)
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	2	-	not specified (3)
-	1	-	Ataxia-telangiectasia syndrome;C0346153:Familial cancer of breast (1)
-	1	-	Breast and/or ovarian cancer (1)
-	1	-	Familial cancer of breast (1)
-	-	1	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.095	N
PhyloP100		10
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.0	N
REVEL	Uncertain	0.47
Sift	Benign	0.22	T
Sift4G	Benign	0.35	T
Polyphen		0.77	P
Vest4		0.88
MutPred		0.79		Loss of helix (P = 0.2271)
MVP		0.91
MPC		0.22
ClinPred		0.10	T
GERP RS		5.5
Varity_R		0.56
gMVP		0.69
Mutation Taster		=36/64	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: rs529296539; hg19: chr11-108216546; COSMIC: COSV53749441;