11-108317312-C-G

Variant names:

• chr11-108317312-C-G
• rs17107917
• NM_000051.4:c.6199-61C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.6199-61C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,536,150 control chromosomes in the GnomAD database, including 1,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (107 hom., cov: 28)
  • Exomes 𝑓: 0.038 (1094 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.214
• Publications: 8 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 (BayesDel_noAF=-0.81).
• BP6: Variant 11-108317312-C-G is Benign according to our data. Variant chr11-108317312-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1228645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.6199-61C>G		intron_variant	Intron 42 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.6199-61C>G		intron_variant	Intron 42 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0298 AC: 4518 AN: 151738 Hom.: 107 Cov.: 28

Gnomad AFR AF: 0.00665

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.0288

Gnomad FIN AF: 0.0382

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0455

Gnomad OTH AF: 0.0302

GnomAD4 exome AF: 0.0379 AC: 52526 AN: 1384294 Hom.: 1094 AF XY: 0.0380 AC XY: 26247 AN XY: 691042

African (AFR) AF: 0.00619 AC: 192 AN: 30994

American (AMR) AF: 0.0214 AC: 886 AN: 41338

Ashkenazi Jewish (ASJ) AF: 0.0465 AC: 1153 AN: 24806

East Asian (EAS) AF: 0.000131 AC: 5 AN: 38152

South Asian (SAS) AF: 0.0299 AC: 2468 AN: 82438

European-Finnish (FIN) AF: 0.0397 AC: 2024 AN: 50990

Middle Eastern (MID) AF: 0.0688 AC: 379 AN: 5506

European-Non Finnish (NFE) AF: 0.0411 AC: 43268 AN: 1053184

Other (OTH) AF: 0.0378 AC: 2151 AN: 56886

GnomAD4 genome AF: 0.0297 AC: 4517 AN: 151856 Hom.: 107 Cov.: 28 AF XY: 0.0298 AC XY: 2213 AN XY: 74180

African (AFR) AF: 0.00663 AC: 275 AN: 41452

American (AMR) AF: 0.0234 AC: 357 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3468

East Asian (EAS) AF: 0.000775 AC: 4 AN: 5160

South Asian (SAS) AF: 0.0287 AC: 138 AN: 4816

European-Finnish (FIN) AF: 0.0382 AC: 401 AN: 10496

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0455 AC: 3093 AN: 67924

Other (OTH) AF: 0.0304 AC: 64 AN: 2106

Alfa AF: 0.0371 Hom.: 17

Bravo AF: 0.0266

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.4
DANN	Benign	0.55
PhyloP100		-0.21
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs17107917; hg19: chr11-108188039; COSMIC: COSV53727936;