rs189037

Positions:

• chr11-108223106-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.-111G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.497 in 180,500 control chromosomes in the GnomAD database, including 24,138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (20089 hom., cov: 32)
  • Exomes 𝑓: 0.52 (4049 hom.)
• Consequence: ATM NM_000051.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.618

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 11-108223106-G-A is Benign according to our data. Variant chr11-108223106-G-A is described in ClinVar as [Benign]. Clinvar id is 302240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108223106-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.-111G>A		5_prime_UTR_variant	1/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.-111G>A		5_prime_UTR_variant	1/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74964 AN: 151940 Hom.: 20079 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.610

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.732

Gnomad NFE AF: 0.568

Gnomad OTH AF: 0.539

GnomAD4 exome AF: 0.515 AC: 14650 AN: 28442 Hom.: 4049 Cov.: 0 AF XY: 0.523 AC XY: 8065 AN XY: 15418

Gnomad4 AFR exome AF: 0.204

Gnomad4 AMR exome AF: 0.615

Gnomad4 ASJ exome AF: 0.544

Gnomad4 EAS exome AF: 0.384

Gnomad4 SAS exome AF: 0.555

Gnomad4 FIN exome AF: 0.507

Gnomad4 NFE exome AF: 0.502

Gnomad4 OTH exome AF: 0.512

GnomAD4 genome AF: 0.493 AC: 74993 AN: 152058 Hom.: 20089 Cov.: 32 AF XY: 0.502 AC XY: 37304 AN XY: 74322

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.610

Gnomad4 ASJ AF: 0.642

Gnomad4 EAS AF: 0.423

Gnomad4 SAS AF: 0.601

Gnomad4 FIN AF: 0.630

Gnomad4 NFE AF: 0.568

Gnomad4 OTH AF: 0.540

Alfa AF: 0.520 Hom.: 2904

Bravo AF: 0.480

Asia WGS AF: 0.534 AC: 1854 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 20816691, 22529920, 22960875, 20004998, 21108427, 23993922, 21937043) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	9.8
DANN	Benign	0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs189037; hg19: chr11-108093833; COSMIC: COSV53716927; COSMIC: COSV53716927;