NM_000051.4:c.*548G>T

Variant names:

• chr11-108366056-G-T
• rs227092
• NM_000051.4:c.*548G>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.*548G>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 0.522 in 171,628 control chromosomes in the GnomAD database, including 24,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21088 hom., cov: 26)
  • Exomes 𝑓: 0.51 (3295 hom.)
• Consequence: ATM NM_000051.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.02
• Publications: 25 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 11-108366056-G-T is Benign according to our data. Variant chr11-108366056-G-T is described in ClinVar as Benign. ClinVar VariationId is 302265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	NM_000051.4	MANE Select	c.*548G>T		3_prime_UTR	Exon 63 of 63	NP_000042.3
	ATM	NM_001351834.2		c.*548G>T		3_prime_UTR	Exon 64 of 64	NP_001338763.1
	C11orf65	NM_001330368.2		c.640+19864C>A		intron	N/A	NP_001317297.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.*548G>T		3_prime_UTR	Exon 63 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.*548G>T		3_prime_UTR	Exon 64 of 64	ENSP00000388058.2
	C11orf65	ENST00000615746.4	TSL:1	c.*2-9947C>A		intron	N/A	ENSP00000483537.1

Frequencies

GnomAD3 genomes AF: 0.523 AC: 77368 AN: 147952 Hom.: 21084 Cov.: 26

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.643

Gnomad AMR AF: 0.614

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.735

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.558

GnomAD4 exome AF: 0.515 AC: 12156 AN: 23614 Hom.: 3295 Cov.: 0 AF XY: 0.518 AC XY: 5627 AN XY: 10872

African (AFR) AF: 0.358 AC: 327 AN: 914

American (AMR) AF: 0.529 AC: 294 AN: 556

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 779 AN: 1334

East Asian (EAS) AF: 0.460 AC: 2280 AN: 4952

South Asian (SAS) AF: 0.580 AC: 130 AN: 224

European-Finnish (FIN) AF: 0.389 AC: 7 AN: 18

Middle Eastern (MID) AF: 0.682 AC: 90 AN: 132

European-Non Finnish (NFE) AF: 0.538 AC: 7320 AN: 13610

Other (OTH) AF: 0.496 AC: 929 AN: 1874

GnomAD4 genome AF: 0.523 AC: 77377 AN: 148014 Hom.: 21088 Cov.: 26 AF XY: 0.531 AC XY: 38037 AN XY: 71670

African (AFR) AF: 0.370 AC: 14890 AN: 40280

American (AMR) AF: 0.614 AC: 9009 AN: 14678

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2217 AN: 3458

East Asian (EAS) AF: 0.432 AC: 2152 AN: 4980

South Asian (SAS) AF: 0.650 AC: 3080 AN: 4740

European-Finnish (FIN) AF: 0.625 AC: 5685 AN: 9096

Middle Eastern (MID) AF: 0.723 AC: 204 AN: 282

European-Non Finnish (NFE) AF: 0.569 AC: 38406 AN: 67536

Other (OTH) AF: 0.559 AC: 1150 AN: 2056

Alfa AF: 0.400 Hom.: 1270

Bravo AF: 0.513

Asia WGS AF: 0.566 AC: 1970 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ataxia-telangiectasia syndrome Benign:1

Jan 12, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.093
DANN	Benign	0.36
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs227092; hg19: chr11-108236783;