11-108317539-A-ATTT

Variant names:

• chr11-108317539-A-ATTT
• rs58978479
• NM_000051.4:c.6347+29_6347+31dupTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000051.4(ATM):​c.6347+29_6347+31dupTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000168 in 1,193,238 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.405
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.6347+29_6347+31dupTTT		intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.6347+29_6347+31dupTTT		intron	N/A	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-8471_641-8469dupAAA		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.6347+18_6347+19insTTT		intron	N/A	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.6347+18_6347+19insTTT		intron	N/A	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*1411+18_*1411+19insTTT		intron	N/A	ENSP00000435747.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000168 AC: 2 AN: 1193238 Hom.: 0 Cov.: 0 AF XY: 0.00000336 AC XY: 2 AN XY: 595350

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28950

American (AMR) AF: 0.00 AC: 0 AN: 37684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30904

South Asian (SAS) AF: 0.00 AC: 0 AN: 73556

European-Finnish (FIN) AF: 0.0000241 AC: 1 AN: 41430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4912

European-Non Finnish (NFE) AF: 0.00000110 AC: 1 AN: 905502

Other (OTH) AF: 0.00 AC: 0 AN: 48932

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.41

Splicing

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

Other links and lift over

dbSNP: rs58978479; hg19: chr11-108188266;