rs761790685

Variant names:

• chr11-108331988-G-A
• rs761790685
• NM_000051.4:c.7739G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-108331988-G-A
• chr11-108331988-G-C
• chr11-108331988-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000051.4(ATM):​c.7739G>A​(p.Arg2580Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R2580S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5
• Conservation: PhyloP100: 4.45
• Publications: 2 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.7739G>A	p.Arg2580Lys	missense	Exon 52 of 63	NP_000042.3
	ATM	NM_001351834.2		c.7739G>A	p.Arg2580Lys	missense	Exon 53 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-22917C>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.7739G>A	p.Arg2580Lys	missense	Exon 52 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.7739G>A	p.Arg2580Lys	missense	Exon 53 of 64	ENSP00000388058.2
	C11orf65	ENST00000615746.4	TSL:1	c.*1270-421C>T		intron	N/A	ENSP00000483537.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251114 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461754 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727170

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111944

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Ataxia-telangiectasia syndrome (2)
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	1	-	Familial colorectal cancer type X (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.81
DEOGEN2	Benign	0.050	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.0018
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.4
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.39	N
REVEL	Uncertain	0.30
Sift	Benign	0.28	T
Sift4G	Benign	0.65	T
Polyphen		0.0020	B
Vest4		0.41
MutPred		0.45		Gain of methylation at R2580 (P = 0.0177)
MVP		0.85
MPC		0.13
ClinPred		0.096	T
GERP RS		5.3
Varity_R		0.15
gMVP		0.45
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.34		Position offset: 49

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs761790685; hg19: chr11-108202715;