11-108297401-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000051.4(ATM):​c.5005+19C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,408,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

ATM
NM_000051.4 intron

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.650
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP6
Variant 11-108297401-C-G is Benign according to our data. Variant chr11-108297401-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420913.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATMNM_000051.4 linkuse as main transcriptc.5005+19C>G intron_variant ENST00000675843.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATMENST00000675843.1 linkuse as main transcriptc.5005+19C>G intron_variant NM_000051.4 P1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000400
AC:
1
AN:
249770
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135086
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000497
AC:
7
AN:
1408198
Hom.:
0
Cov.:
25
AF XY:
0.00000569
AC XY:
4
AN XY:
703598
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000282
Gnomad4 OTH exome
AF:
0.0000512
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 21, 2017This variant is denoted ATM c.5005+19C>G or IVS33+19C>G and consists of a C>G nucleotide substitution at the +19 position of intron 33 of the ATM gene. Multiple in silico models predict this variant to create a cryptic splice donor site and possibly causing abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown.? This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM c.5005+19C>G was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). The cytosine (C) nucleotide that is altered is not conserved. Based on currently available evidence, it is unclear whether ATM c.5005+19C>G is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthSep 08, 2020This variant causes a C to G nucleotide substitution at the +19 position of intron 33 of the ATM gene. Splice site prediction tools predict that this variant may impact RNA splicing due to the creation of a new splice donor site. To our knowledge, this prediction has not been investigated in published RNA studies. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/249770 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Ataxia-telangiectasia syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.90
CADD
Benign
17
DANN
Benign
0.25
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.45
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.45
Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1064794787; hg19: chr11-108168128; API