11-108315883-G-A

Variant names:

• chr11-108315883-G-A
• rs11212587
• NM_000051.4:c.6067G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_000051.4(ATM):​c.6067G>A​(p.Gly2023Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,612,772 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2023E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (4 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:22 O:3
• Conservation: PhyloP100: 9.47
• Publications: 68 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: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 3 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=0.15664351).
• BP6: Variant 11-108315883-G-A is Benign according to our data. Variant chr11-108315883-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127416.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00125 (190/152254) while in subpopulation NFE AF = 0.00226 (154/68028). AF 95% confidence interval is 0.00197. There are 0 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.6067G>A	p.Gly2023Arg	missense	Exon 41 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6067G>A	p.Gly2023Arg	missense	Exon 42 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-6812C>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.6067G>A	p.Gly2023Arg	missense	Exon 41 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.6067G>A	p.Gly2023Arg	missense	Exon 42 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*1131G>A		non_coding_transcript_exon	Exon 39 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00226

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00143 AC: 360 AN: 251402 AF XY: 0.00150

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00238

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00158 AC: 2306 AN: 1460518 Hom.: 4 Cov.: 32 AF XY: 0.00159 AC XY: 1152 AN XY: 726704

African (AFR) AF: 0.000269 AC: 9 AN: 33460

American (AMR) AF: 0.000962 AC: 43 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000626 AC: 54 AN: 86218

European-Finnish (FIN) AF: 0.000899 AC: 48 AN: 53410

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5762

European-Non Finnish (NFE) AF: 0.00183 AC: 2034 AN: 1110788

Other (OTH) AF: 0.00179 AC: 108 AN: 60346

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74436

African (AFR) AF: 0.000313 AC: 13 AN: 41542

American (AMR) AF: 0.000785 AC: 12 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00226 AC: 154 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00193 Hom.: 5

Bravo AF: 0.00132

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00157 AC: 191

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00225

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	9	not provided (11)
-	3	3	Hereditary cancer-predisposing syndrome (6)
-	1	4	Ataxia-telangiectasia syndrome (6)
-	-	3	not specified (4)
-	1	1	Familial cancer of breast (2)
-	-	1	Breast and/or ovarian cancer (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.54		Loss of ubiquitination at K2025 (P = 0.0258)
MVP		0.96
MPC		0.62
ClinPred		0.056	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.70
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11212587; hg19: chr11-108186610;