11-108304817-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000051.4(ATM):c.5639C>G(p.Thr1880Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1880M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077608824).
• BP6: Variant 11-108304817-C-G is Benign according to our data. Variant chr11-108304817-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.5639C>G	p.Thr1880Arg	missense_variant	37/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.5639C>G	p.Thr1880Arg	missense_variant	37/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152004 Hom.: 0 Cov.: 32 FAILED QC

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0144 AC: 2988 AN: 208108 Hom.: 0 AF XY: 0.0142 AC XY: 1608 AN XY: 113412

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.00226

Gnomad EAS exome AF: 0.0293

Gnomad SAS exome AF: 0.00652

Gnomad FIN exome AF: 0.0239

Gnomad NFE exome AF: 0.0139

Gnomad OTH exome AF: 0.00626

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00129 AC: 1848 AN: 1434306 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 976 AN XY: 712268

Gnomad4 AFR exome AF: 0.00455

Gnomad4 AMR exome AF: 0.00728

Gnomad4 ASJ exome AF: 0.000156

Gnomad4 EAS exome AF: 0.00713

Gnomad4 SAS exome AF: 0.00169

Gnomad4 FIN exome AF: 0.00703

Gnomad4 NFE exome AF: 0.000558

Gnomad4 OTH exome AF: 0.000840

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 152004 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74240

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00148 Hom.: 0

ExAC AF: 0.00115 AC: 140

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	15
Dann	Benign	0.97
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.32	T;.
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.070
Sift	Benign	0.093	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.051	B;B
Vest4		0.18
MPC		0.14
ClinPred		0.0065	T
GERP RS		2.5
Varity_R		0.037
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780628; hg19: chr11-108175544; COSMIC: COSV53727903; COSMIC: COSV53727903;