rs1555101600

Variant names:

• chr11-108294917-TCTC-CTCTTTTAGTTACATTTACATTTTAGTTAA
• rs1555101600
• NM_000051.4:c.4777-10_4777-7delTCTCinsCTCTTTTAGTTACATTTACATTTTAGTTAA

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000051.4(ATM):​c.4777-10_4777-7delTCTCinsCTCTTTTAGTTACATTTACATTTTAGTTAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 0.716

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
• PP5: Variant 11-108294917-TCTC-CTCTTTTAGTTACATTTACATTTTAGTTAA is Pathogenic according to our data. Variant chr11-108294917-TCTC-CTCTTTTAGTTACATTTACATTTTAGTTAA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 489549.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.4777-10_4777-7delTCTCinsCTCTTTTAGTTACATTTACATTTTAGTTAA		splice_region_variant, intron_variant	Intron 31 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4777-10_4777-7delTCTCinsCTCTTTTAGTTACATTTACATTTTAGTTAA		splice_region_variant, intron_variant	Intron 31 of 62		NM_000051.4	ENSP00000501606.1

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1 Uncertain:1

Jun 04, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes the deletion of 4 nucleotides and insertion of 30 nucleotides in intron 31/62 of the ATM gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant has been reported to impact RNA splicing by an external laboratory, however, detailed data are not available for review (ClinVar Accession: SCV005017347.1). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Oct 26, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4777-10_4777-7delTCTCins30 intronic variant begins 10 nucleotides before coding exon 31 in the ATM gene. This variant results from a deletion of 4 nucleotides and the insertion of 30 nucleotides at nucleotide positions c.4777-10 to c.4777-7. This nucleotide region is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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: rs1555101600; hg19: chr11-108165644;