rs373759

Variant names:

• chr11-108349930-C-T
• rs373759
• NM_000051.4:c.8671+2565C>T

Variant summary

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

The NM_000051.4(ATM):​c.8671+2565C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 151,832 control chromosomes in the GnomAD database, including 7,170 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 0.28 (7170 hom., cov: 32)
• Consequence: ATM NM_000051.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.66
• Publications: 30 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=-0.96).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.473 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.8671+2565C>T		intron_variant	Intron 59 of 62	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.8671+2565C>T		intron_variant	Intron 59 of 62		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.282 AC: 42711 AN: 151714 Hom.: 7171 Cov.: 32

Gnomad AFR AF: 0.0993

Gnomad AMI AF: 0.226

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.358

Gnomad SAS AF: 0.488

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.532

Gnomad NFE AF: 0.328

Gnomad OTH AF: 0.325

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

GnomAD4 genome AF: 0.281 AC: 42710 AN: 151832 Hom.: 7170 Cov.: 32 AF XY: 0.291 AC XY: 21556 AN XY: 74184

African (AFR) AF: 0.0990 AC: 4098 AN: 41404

American (AMR) AF: 0.406 AC: 6196 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1351 AN: 3466

East Asian (EAS) AF: 0.358 AC: 1842 AN: 5148

South Asian (SAS) AF: 0.489 AC: 2354 AN: 4814

European-Finnish (FIN) AF: 0.339 AC: 3566 AN: 10506

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.328 AC: 22251 AN: 67940

Other (OTH) AF: 0.329 AC: 694 AN: 2108

Alfa AF: 0.308 Hom.: 1410

Bravo AF: 0.275

Asia WGS AF: 0.443 AC: 1537 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.75
DANN	Benign	0.41
PhyloP100		-1.7
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: rs373759; hg19: chr11-108220657;