rs1064792939

Positions:

• chr11-108301788-AGGTCTCTTA-ATGTTTG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000051.4(ATM):​c.5319_5319+8delinsTGTTTG variant causes a splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.18

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.5319_5319+8delinsTGTTTG		splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	35/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.5319_5319+8delinsTGTTTG		splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	35/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 02, 2018

This variant is denoted ATM c.5319_5319+8delGGTCTCTTAinsTGTTTG at the cDNA level. The surrounding sequence is GAAAAAA[delGgtctctta][insTgtttg]agta, where the capital letters are exonic and lower case are intronic. Although this combined deletion and insertion spans the intron/exon boundary including the canonical splice site, a 'GT' is retained at the canonical +1 and +2 positions. In silico analyses, which include splice predictors and evolutionary conservation, are uninformative in their assessment as to whether or not the variant is damaging; therefore, in the absence of RNA or functional studies, the actual effect of this variant is unknown. ATM c.5319_5319+8delGGTCTCTTAinsTGTTTG has not, to our knowledge, been reported in the literature as pathogenic or benign. This variant was not observed in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether this variant 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 submitter

clinical testing

Ambry Genetics

Mar 31, 2021

The c.5319_5319+8delinsTGTTTG variant results from a deletion of 9 nucleotides and insertion of 6 nucleotides between positions c.5319 and c.5319+8. This variant involves the last nucleotide of coding exon 35 of the ATM gene but maintains the sequence of the canonical positions at this donor site. The last nucleotide is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064792939; hg19: chr11-108172516;