11-108325782-G-C

Variant names:

• chr11-108325782-G-C
• rs609429
• NM_000051.4:c.6807+238G>C

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.6807+238G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.537 in 151,936 control chromosomes in the GnomAD database, including 22,539 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.54 (22539 hom., cov: 31)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.20
• Publications: 27 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=-0.91).
• BP6: Variant 11-108325782-G-C is Benign according to our data. Variant chr11-108325782-G-C is described in ClinVar as Benign. ClinVar VariationId is 632649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.6807+238G>C		intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.6807+238G>C		intron	N/A	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-16711C>G		intron	N/A	NP_001317297.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.6807+238G>C		intron	N/A	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.6807+238G>C		intron	N/A	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*1871+238G>C		intron	N/A	ENSP00000435747.2

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81614 AN: 151820 Hom.: 22527 Cov.: 31

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.570

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.537 AC: 81653 AN: 151936 Hom.: 22539 Cov.: 31 AF XY: 0.545 AC XY: 40478 AN XY: 74252

African (AFR) AF: 0.416 AC: 17243 AN: 41414

American (AMR) AF: 0.623 AC: 9520 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2223 AN: 3470

East Asian (EAS) AF: 0.435 AC: 2247 AN: 5164

South Asian (SAS) AF: 0.650 AC: 3128 AN: 4810

European-Finnish (FIN) AF: 0.631 AC: 6648 AN: 10544

Middle Eastern (MID) AF: 0.747 AC: 218 AN: 292

European-Non Finnish (NFE) AF: 0.569 AC: 38634 AN: 67952

Other (OTH) AF: 0.571 AC: 1206 AN: 2112

Alfa AF: 0.412 Hom.: 1099

Bravo AF: 0.529

Asia WGS AF: 0.572 AC: 1988 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 27, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ATM c.6807+238G>C is located at a position not widely known to affect splicing. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.53 in 30856 control chromosomes, suggesting that it is the major allele and therefore benign. The observed variant frequency is approximately 133-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Ataxia-Telangiectasia phenotype (0.004), strongly suggesting that the variant is benign. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign.

not provided Benign:1

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.71
DANN	Benign	0.64
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs609429; hg19: chr11-108196509;