rs377648506

Variant names:

• chr11-108333946-T-C
• rs377648506
• NM_000051.4:c.7988T>C
• ATM p.Val2663Ala

Your query was ambiguous. Multiple possible variants found:

• chr11-108333946-T-C
• chr11-108333946-T-A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_000051.4(ATM):​c.7988T>C​(p.Val2663Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,611,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. V2663I) has been classified as Likely benign. The gene ATM is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:4 O:1
• Conservation: PhyloP100: 4.45
• Publications: 5 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_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 39 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.06477538).
• BP6: Variant 11-108333946-T-C is Benign according to our data. Variant chr11-108333946-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133635.

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.7988T>C	p.Val2663Ala	missense	Exon 54 of 63	NP_000042.3
	ATM	NM_001351834.2		c.7988T>C	p.Val2663Ala	missense	Exon 55 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-24875A>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.7988T>C	p.Val2663Ala	missense	Exon 54 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.7988T>C	p.Val2663Ala	missense	Exon 55 of 64	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*1269+1274A>G		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251198 AF XY: 0.0000516

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1458834 Hom.: 0 Cov.: 30 AF XY: 0.00000964 AC XY: 7 AN XY: 725904

African (AFR) AF: 0.000329 AC: 11 AN: 33406

American (AMR) AF: 0.0000894 AC: 4 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109308

Other (OTH) AF: 0.0000664 AC: 4 AN: 60278

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74490

African (AFR) AF: 0.000361 AC: 15 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

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

Alfa AF: 0.000165 Hom.: 0

Bravo AF: 0.000159

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Ataxia-telangiectasia syndrome (3)
-	2	1	Familial cancer of breast (3)
-	3	-	not provided (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	ATM-related disorder (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	1	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.71	N
PhyloP100		4.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.21
Sift	Benign	0.56	T
Sift4G	Benign	0.61	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.080
gMVP		0.42
Mutation Taster		=61/39	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs377648506;

hg19: chr11-108204673;