11-108271253-A-T

Variant names:

• chr11-108271253-A-T
• rs730881354
• NM_000051.4:c.2924A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000051.4(ATM):​c.2924A>T​(p.Asn975Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N975K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATM NM_000051.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.17
• Publications: 0 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]

ATM Gene-Disease associations (from GenCC):

• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• ataxia telangiectasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Laboratory for Molecular Medicine, Orphanet
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• familial ovarian cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• gastric carcinoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 41 uncertain in NM_000051.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.15383941).

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.2924A>T	p.Asn975Ile	missense splice_region	Exon 20 of 63	NP_000042.3
	ATM	NM_001351834.2		c.2924A>T	p.Asn975Ile	missense splice_region	Exon 21 of 64	NP_001338763.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATM	ENST00000675843.1	MANE Select	c.2924A>T	p.Asn975Ile	missense splice_region	Exon 20 of 63	ENSP00000501606.1
	ATM	ENST00000452508.7	TSL:1	c.2924A>T	p.Asn975Ile	missense splice_region	Exon 21 of 64	ENSP00000388058.2
	ATM	ENST00000531525.3	TSL:1	c.2924A>T	p.Asn975Ile	missense splice_region	Exon 20 of 30	ENSP00000434327.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151408 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1461496 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727032

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111896

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 151408 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73886

African (AFR) AF: 0.00 AC: 0 AN: 41208

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67874

Other (OTH) AF: 0.00 AC: 0 AN: 2082

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.2
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.11
Sift	Benign	0.17	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.45		Gain of sheet (P = 0.0061)
MVP		0.73
MPC		0.16
ClinPred		0.85	D
GERP RS		3.1
Varity_R		0.16
gMVP		0.10
Mutation Taster		=85/15	polymorphism

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: rs730881354; hg19: chr11-108141980;