11-108325482-G-C

Variant names:

• chr11-108325482-G-C
• NM_000051.4:c.6745G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000051.4(ATM):​c.6745G>C​(p.Asp2249His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ATM NM_000051.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATM	NM_000051.4	c.6745G>C	p.Asp2249His	missense_variant	Exon 46 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.6745G>C	p.Asp2249His	missense_variant	Exon 46 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D2249H variant (also known as c.6745G>C), located in coding exon 45 of the ATM gene, results from a G to C substitution at nucleotide position 6745. The aspartic acid at codon 2249 is replaced by histidine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	D;.
M_CAP	Uncertain	0.093	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.38
MutPred		0.65		Loss of ubiquitination at K2253 (P = 0.0438);Loss of ubiquitination at K2253 (P = 0.0438);
MVP		0.90
MPC		0.50
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.17
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-108196209;