11-108236055-C-T

Variant names:

• chr11-108236055-C-T
• rs623860
• NM_000051.4:c.496+221C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.496+221C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.611 in 551,504 control chromosomes in the GnomAD database, including 104,616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (32708 hom., cov: 32)
  • Exomes 𝑓: 0.60 (71908 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.342
• Publications: 14 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]

ATM Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-108236055-C-T is Benign according to our data. Variant chr11-108236055-C-T is described in ClinVar as Benign. ClinVar VariationId is 1220661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.496+221C>T		intron_variant	Intron 5 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.496+221C>T		intron_variant	Intron 5 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98536 AN: 151882 Hom.: 32657 Cov.: 32

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.646

Gnomad AMR AF: 0.676

Gnomad ASJ AF: 0.673

Gnomad EAS AF: 0.446

Gnomad SAS AF: 0.653

Gnomad FIN AF: 0.631

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.655

GnomAD4 exome AF: 0.597 AC: 238483 AN: 399502 Hom.: 71908 Cov.: 4 AF XY: 0.601 AC XY: 127821 AN XY: 212720

African (AFR) AF: 0.784 AC: 8902 AN: 11352

American (AMR) AF: 0.671 AC: 11229 AN: 16742

Ashkenazi Jewish (ASJ) AF: 0.650 AC: 7818 AN: 12036

East Asian (EAS) AF: 0.472 AC: 12114 AN: 25688

South Asian (SAS) AF: 0.649 AC: 28535 AN: 43996

European-Finnish (FIN) AF: 0.627 AC: 14158 AN: 22582

Middle Eastern (MID) AF: 0.760 AC: 1324 AN: 1742

European-Non Finnish (NFE) AF: 0.579 AC: 140404 AN: 242432

Other (OTH) AF: 0.610 AC: 13999 AN: 22932

GnomAD4 genome AF: 0.649 AC: 98639 AN: 152002 Hom.: 32708 Cov.: 32 AF XY: 0.653 AC XY: 48480 AN XY: 74264

African (AFR) AF: 0.783 AC: 32484 AN: 41494

American (AMR) AF: 0.675 AC: 10307 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.673 AC: 2337 AN: 3472

East Asian (EAS) AF: 0.446 AC: 2303 AN: 5160

South Asian (SAS) AF: 0.654 AC: 3151 AN: 4818

European-Finnish (FIN) AF: 0.631 AC: 6663 AN: 10554

Middle Eastern (MID) AF: 0.762 AC: 224 AN: 294

European-Non Finnish (NFE) AF: 0.577 AC: 39201 AN: 67934

Other (OTH) AF: 0.656 AC: 1382 AN: 2108

Alfa AF: 0.601 Hom.: 14516

Bravo AF: 0.655

Asia WGS AF: 0.608 AC: 2115 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.9
DANN	Benign	0.49
PhyloP100		0.34
Mutation Taster		=98/2	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: rs623860; hg19: chr11-108106782;