NM_000051.4:c.7919C>T

Variant names:

• chr11-108332892-C-T
• rs4988125
• NM_000051.4:c.7919C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_000051.4(ATM):​c.7919C>T​(p.Thr2640Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,612,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. T2640S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:9 O:1
• Conservation: PhyloP100: 0.270
• Publications: 16 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 33 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.12590104).
• BP6: Variant 11-108332892-C-T is Benign according to our data. Variant chr11-108332892-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133634.

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.7919C>T	p.Thr2640Ile	missense	Exon 53 of 63	NP_000042.3
	ATM	NM_001351834.2		c.7919C>T	p.Thr2640Ile	missense	Exon 54 of 64	NP_001338763.1	Q13315
	C11orf65	NM_001330368.2		c.641-23821G>A		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.7919C>T	p.Thr2640Ile	missense	Exon 53 of 63	ENSP00000501606.1	Q13315
	ATM	ENST00000452508.7	TSL:1	c.7919C>T	p.Thr2640Ile	missense	Exon 54 of 64	ENSP00000388058.2	Q13315
	C11orf65	ENST00000615746.4	TSL:1	c.*1270-1325G>A		intron	N/A	ENSP00000483537.1	Q8NCR3-1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000959 AC: 24 AN: 250134 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000481

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000241 AC: 352 AN: 1460112 Hom.: 0 Cov.: 31 AF XY: 0.000231 AC XY: 168 AN XY: 726474

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.0000383 AC: 2 AN: 52266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.000310 AC: 345 AN: 1111620

Other (OTH) AF: 0.0000663 AC: 4 AN: 60350

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74292

African (AFR) AF: 0.00 AC: 0 AN: 41410

American (AMR) AF: 0.00 AC: 0 AN: 15266

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000184 Hom.: 0

Bravo AF: 0.000117

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	3	not provided (7)
-	2	2	Hereditary cancer-predisposing syndrome (4)
-	-	3	Ataxia-telangiectasia syndrome (3)
-	1	1	Familial cancer of breast (2)
-	2	-	not specified (3)
-	1	-	Malignant tumor of breast (1)
-	1	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.27
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.14
Sift	Benign	0.11	T
Sift4G	Benign	0.13	T
Polyphen		0.49	P
Vest4		0.21
MVP		0.77
MPC		0.15
ClinPred		0.13	T
GERP RS		2.1
Varity_R		0.075
gMVP		0.34
Mutation Taster		=73/27	polymorphism

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: rs4988125; hg19: chr11-108203619; COSMIC: COSV99069684;