rs227074

Variant names:

• chr11-108344368-A-G
• rs227074
• NM_000051.4:c.8418+997A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000051.4(ATM):​c.8418+997A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 151,964 control chromosomes in the GnomAD database, including 22,681 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (22681 hom., cov: 31)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.197
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.8418+997A>G		intron_variant	Intron 57 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8418+997A>G		intron_variant	Intron 57 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.540 AC: 81992 AN: 151846 Hom.: 22668 Cov.: 31

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.436

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.571

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.540 AC: 82033 AN: 151964 Hom.: 22681 Cov.: 31 AF XY: 0.547 AC XY: 40651 AN XY: 74252

African (AFR) AF: 0.425 AC: 17620 AN: 41460

American (AMR) AF: 0.623 AC: 9514 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2222 AN: 3468

East Asian (EAS) AF: 0.437 AC: 2248 AN: 5148

South Asian (SAS) AF: 0.650 AC: 3133 AN: 4818

European-Finnish (FIN) AF: 0.630 AC: 6636 AN: 10540

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.569 AC: 38648 AN: 67952

Other (OTH) AF: 0.571 AC: 1209 AN: 2116

Alfa AF: 0.542 Hom.: 3517

Bravo AF: 0.532

Asia WGS AF: 0.572 AC: 1991 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.6
DANN	Benign	0.42
PhyloP100		-0.20
Mutation Taster		=99/1	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: rs227074; hg19: chr11-108215095;