11-108317539-AT-A

Variant names:

• chr11-108317539-AT-A
• rs58978479
• NM_000051.4:c.6347+31delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.6347+31delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 125,032 control chromosomes in the GnomAD database, including 2,646 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (2646 hom., cov: 24)
  • Exomes 𝑓: 0.21 (851 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.405
• Publications: 4 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 11-108317539-AT-A is Benign according to our data. Variant chr11-108317539-AT-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 522241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

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+31delT		intron	N/A	NP_000042.3
	ATM	NM_001351834.2		c.6347+31delT		intron	N/A	NP_001338763.1
	C11orf65	NM_001330368.2		c.641-8469delA		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+19delT		intron	N/A	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.6347+19delT		intron	N/A	ENSP00000388058.2
	ATM	ENST00000527805.6	TSL:1	n.*1411+19delT		intron	N/A	ENSP00000435747.2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 15300 AN: 125012 Hom.: 2643 Cov.: 24

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.00256

Gnomad AMR AF: 0.0625

Gnomad ASJ AF: 0.0339

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.00405

Gnomad FIN AF: 0.00201

Gnomad MID AF: 0.0391

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0958

GnomAD2 exomes AF: 0.335 AC: 34114 AN: 101888 AF XY: 0.332

Gnomad AFR exome AF: 0.498

Gnomad AMR exome AF: 0.377

Gnomad ASJ exome AF: 0.411

Gnomad EAS exome AF: 0.314

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.288

Gnomad OTH exome AF: 0.341

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.207 AC: 176126 AN: 851688 Hom.: 851 Cov.: 0 AF XY: 0.209 AC XY: 87545 AN XY: 418412

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

African (AFR) AF: 0.439 AC: 11600 AN: 26418

American (AMR) AF: 0.258 AC: 7216 AN: 28016

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 4153 AN: 15308

East Asian (EAS) AF: 0.240 AC: 5864 AN: 24404

South Asian (SAS) AF: 0.239 AC: 11596 AN: 48456

European-Finnish (FIN) AF: 0.210 AC: 6596 AN: 31450

Middle Eastern (MID) AF: 0.166 AC: 665 AN: 4002

European-Non Finnish (NFE) AF: 0.188 AC: 119915 AN: 637216

Other (OTH) AF: 0.234 AC: 8521 AN: 36418

⚠️ 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 AF: 0.123 AC: 15317 AN: 125032 Hom.: 2646 Cov.: 24 AF XY: 0.119 AC XY: 7133 AN XY: 59914

African (AFR) AF: 0.392 AC: 13583 AN: 34674

American (AMR) AF: 0.0624 AC: 743 AN: 11908

Ashkenazi Jewish (ASJ) AF: 0.0339 AC: 104 AN: 3068

East Asian (EAS) AF: 0.0123 AC: 52 AN: 4244

South Asian (SAS) AF: 0.00356 AC: 14 AN: 3930

European-Finnish (FIN) AF: 0.00201 AC: 13 AN: 6462

Middle Eastern (MID) AF: 0.0424 AC: 10 AN: 236

European-Non Finnish (NFE) AF: 0.0110 AC: 636 AN: 58048

Other (OTH) AF: 0.0951 AC: 160 AN: 1682

Alfa AF: 0.117 Hom.: 6

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Ataxia-telangiectasia syndrome (3)
-	-	2	not specified (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs58978479; hg19: chr11-108188266; COSMIC: COSV104377482; COSMIC: COSV104377482;