11-108315904-A-G

Variant names:

• chr11-108315904-A-G
• rs145847315
• NM_000051.4:c.6088A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000051.4(ATM):​c.6088A>G​(p.Ile2030Val) variant causes a missense change. The variant allele was found at a frequency of 0.000911 in 1,611,198 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2030L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0047 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (12 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26 O:1
• Conservation: PhyloP100: 3.72
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054701567).
• BP6: Variant 11-108315904-A-G is Benign according to our data. Variant chr11-108315904-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 133628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00475 (723/152272) while in subpopulation AFR AF = 0.0166 (688/41556). AF 95% confidence interval is 0.0155. There are 9 homozygotes in GnomAd4. There are 345 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.6088A>G	p.Ile2030Val	missense	Exon 41 of 63	NP_000042.3
	ATM	NM_001351834.2		c.6088A>G	p.Ile2030Val	missense	Exon 42 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-6833T>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.6088A>G	p.Ile2030Val	missense	Exon 41 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.6088A>G	p.Ile2030Val	missense	Exon 42 of 64	ENSP00000388058.2	Q13315
	ATM	ENST00000527805.6	TSL:1	n.*1152A>G		non_coding_transcript_exon	Exon 39 of 61	ENSP00000435747.2	E9PIN0

Frequencies

GnomAD3 genomes AF: 0.00475 AC: 722 AN: 152154 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00126 AC: 318 AN: 251420 AF XY: 0.000927

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000511 AC: 745 AN: 1458926 Hom.: 12 Cov.: 32 AF XY: 0.000415 AC XY: 301 AN XY: 725990

African (AFR) AF: 0.0189 AC: 633 AN: 33412

American (AMR) AF: 0.000805 AC: 36 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.00000811 AC: 9 AN: 1109364

Other (OTH) AF: 0.00105 AC: 63 AN: 60276

GnomAD4 genome AF: 0.00475 AC: 723 AN: 152272 Hom.: 9 Cov.: 32 AF XY: 0.00463 AC XY: 345 AN XY: 74448

African (AFR) AF: 0.0166 AC: 688 AN: 41556

American (AMR) AF: 0.00144 AC: 22 AN: 15292

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.000787 Hom.: 6

Bravo AF: 0.00553

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00161 AC: 195

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (8)
-	-	5	Ataxia-telangiectasia syndrome (5)
-	-	5	Hereditary cancer-predisposing syndrome (5)
-	-	4	not provided (4)
-	-	2	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.066	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.7
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.15
Sift	Benign	0.40	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.098
MVP		0.79
MPC		0.10
ClinPred		0.0056	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.20
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs145847315; hg19: chr11-108186631;