rs183214437

Positions:

• chr11-108289034-A-G
• chr11-108289034-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000051.4(ATM):​c.4167A>G​(p.Thr1389=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,613,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: ATM NM_000051.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.518

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 11-108289034-A-G is Benign according to our data. Variant chr11-108289034-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.518 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATM	NM_000051.4	c.4167A>G	p.Thr1389=	synonymous_variant	28/63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4167A>G	p.Thr1389=	synonymous_variant	28/63		NM_000051.4	ENSP00000501606	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251278 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135800

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.000244 AC: 357 AN: 1461056 Hom.: 0 Cov.: 31 AF XY: 0.000239 AC XY: 174 AN XY: 726914

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000308

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000192 Hom.: 0

Bravo AF: 0.000121

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The ATM p.Thr1389= variant was not identified in the literature nor was it identified in the Genesight-COGR, Cosmic, MutDB, LOVD 3.0, ATM-LOVD, databases. The variant was identified in dbSNP (ID: rs183214437) as “with other allele”, in ClinVar and Clinvitae databases as benign by GeneDx and Ambry Genetics; and likely benign by Invitae, and Color Genomics Inc.). The variant was identified in control databases in 29 of 277012 chromosomes at a frequency of 0.0001 in the following populations: African in 1 of 24024 chromosomes (freq. 0.00004), Latino in 7 of 34400 chromosomes (freq. 0.0002), European Non-Finnish in 18 of 126560 chromosomes (freq. 0.0001), Other in 3of 6458 chromosomes (freq. 0.0005), but was not seen in Ashkenazi Jewish, East Asian , European Finnish, and South Asian populations, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Thr1389= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 13, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 20, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 22, 2021	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 10, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Feb 27, 2024	- -

Ataxia-telangiectasia syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	ATM: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 14, 2021	- -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

May 16, 2024

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.3
DANN	Benign	0.72

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: rs183214437; hg19: chr11-108159761;