rs2234996

Positions:

• chr11-108235599-A-G
• chr11-108235599-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000051.4(ATM):​c.332-71A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,330,594 control chromosomes in the GnomAD database, including 1,091 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (64 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1027 hom.)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.21

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 11-108235599-A-G is Benign according to our data. Variant chr11-108235599-A-G is described in ClinVar as [Benign]. Clinvar id is 1179574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-108235599-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0257 (3920/152360) while in subpopulation SAS AF= 0.0476 (230/4834). AF 95% confidence interval is 0.0425. There are 64 homozygotes in gnomad4. There are 1835 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 64 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.332-71A>G		intron_variant		ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.332-71A>G		intron_variant			NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.0258 AC: 3924 AN: 152242 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00776

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.0795

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0477

Gnomad FIN AF: 0.00791

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0378

Gnomad OTH AF: 0.0320

GnomAD4 exome AF: 0.0371 AC: 43661 AN: 1178234 Hom.: 1027 AF XY: 0.0372 AC XY: 22030 AN XY: 592146

Gnomad4 AFR exome AF: 0.00667

Gnomad4 AMR exome AF: 0.0190

Gnomad4 ASJ exome AF: 0.0834

Gnomad4 EAS exome AF: 0.000142

Gnomad4 SAS exome AF: 0.0455

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.0397

Gnomad4 OTH exome AF: 0.0345

GnomAD4 genome AF: 0.0257 AC: 3920 AN: 152360 Hom.: 64 Cov.: 32 AF XY: 0.0246 AC XY: 1835 AN XY: 74510

Gnomad4 AFR AF: 0.00774

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.0795

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0476

Gnomad4 FIN AF: 0.00791

Gnomad4 NFE AF: 0.0378

Gnomad4 OTH AF: 0.0312

Alfa AF: 0.0348 Hom.: 29

Bravo AF: 0.0262

Asia WGS AF: 0.0210 AC: 72 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.5
DANN	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs2234996; hg19: chr11-108106326; COSMIC: COSV104591951; COSMIC: COSV104591951;