rs1555151422

chr11-108365172-C-Achr11-108365172-C-Gchr11-108365172-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000051.4(ATM):c.8941C>A(p.His2981Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H2981Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049678832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATM	NM_000051.4	c.8941C>A	p.His2981Asn	missense_variant	62/63	ENST00000675843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATM	ENST00000675843.1	c.8941C>A	p.His2981Asn	missense_variant	62/63		NM_000051.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

May 21, 2018

This sequence variant is a single nucleotide substitution (C>A) that results in a histidine to asparagine amino acid change at residue 2981 in the ATM protein. This variant has not, to our knowledge, been observed in literature reports. It is also absent from the ExAC and gnomAD population databases. The His2981 residue is not located in a domain known to be critical for ATM function. Multiple in-silico tools predict that this change will have a neutral effect on the resulting protein. Additionally, this amino acid is not well conserved among mammals; several species, including the elephant, manatee, aardvark, and several marsupials have asparagine in place of histidine for the equivalent amino acid position. This variant does not have an entry in ClinVar. Given the lack of information on this particular variant at this time, we consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
Cadd	Benign	16
Dann	Benign	0.62
DEOGEN2	Benign	0.041	T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.54	T;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.050	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.35	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.47	N;N
REVEL	Benign	0.095
Sift	Benign	0.99	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.17
MutPred		0.34		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP		0.84
MPC		0.14
ClinPred		0.052	T
GERP RS		3.5
Varity_R		0.077
gMVP		0.16

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: rs1555151422; hg19: chr11-108235899;