rs4585

Variant names:

• chr11-108368901-G-T
• rs4585
• NM_000051.4:c.*3393G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000051.4(ATM):​c.*3393G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.54 in 196,746 control chromosomes in the GnomAD database, including 29,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22528 hom., cov: 31)
  • Exomes 𝑓: 0.55 (6782 hom.)
• Consequence: ATM NM_000051.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.343

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 11-108368901-G-T is Benign according to our data. Variant chr11-108368901-G-T is described in ClinVar as [Benign]. Clinvar id is 302299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.*3393G>T		3_prime_UTR_variant	Exon 63 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.*3393G>T		3_prime_UTR_variant	Exon 63 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81603 AN: 151844 Hom.: 22515 Cov.: 31

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.645

Gnomad AMR AF: 0.624

Gnomad ASJ AF: 0.640

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.630

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.570

GnomAD4 exome AF: 0.548 AC: 24543 AN: 44784 Hom.: 6782 Cov.: 0 AF XY: 0.551 AC XY: 11519 AN XY: 20896

Gnomad4 AFR exome AF: 0.418

Gnomad4 AMR exome AF: 0.586

Gnomad4 ASJ exome AF: 0.607

Gnomad4 EAS exome AF: 0.472

Gnomad4 SAS exome AF: 0.633

Gnomad4 FIN exome AF: 0.567

Gnomad4 NFE exome AF: 0.568

Gnomad4 OTH exome AF: 0.536

GnomAD4 genome AF: 0.537 AC: 81644 AN: 151962 Hom.: 22528 Cov.: 31 AF XY: 0.545 AC XY: 40474 AN XY: 74262

Gnomad4 AFR AF: 0.416

Gnomad4 AMR AF: 0.623

Gnomad4 ASJ AF: 0.640

Gnomad4 EAS AF: 0.435

Gnomad4 SAS AF: 0.651

Gnomad4 FIN AF: 0.630

Gnomad4 NFE AF: 0.569

Gnomad4 OTH AF: 0.571

Alfa AF: 0.577 Hom.: 28582

Bravo AF: 0.529

Asia WGS AF: 0.571 AC: 1986 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

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	-0.96
CADD	Benign	1.4
DANN	Benign	0.60

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: rs4585; hg19: chr11-108239628;