11-108289102-C-A

Variant names:

• chr11-108289102-C-A
• NM_000051.4:c.4235C>A

Variant summary

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

The NM_000051.4(ATM):​c.4235C>A​(p.Pro1412His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATM NM_000051.4 missense, splice_region
• Scores: Splicing: ADA: 0.9485
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.52

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 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.4235C>A	p.Pro1412His	missense_variant, splice_region_variant	Exon 28 of 63	ENST00000675843.1	NP_000042.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATM	ENST00000675843.1	c.4235C>A	p.Pro1412His	missense_variant, splice_region_variant	Exon 28 of 63		NM_000051.4	ENSP00000501606.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.87e-7 AC: 1 AN: 1455254 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724328

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

May 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P1412H variant (also known as c.4235C>A), located in coding exon 27 of the ATM gene, results from a C to A substitution at nucleotide position 4235. The proline at codon 1412 is replaced by histidine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D;.;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.9	M;M;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.1	D;D;.
REVEL	Uncertain	0.44
Sift	Benign	0.14	T;T;.
Sift4G	Benign	0.17	T;T;D
Polyphen		0.86	P;P;.
Vest4		0.84
MutPred		0.31		Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);.;
MVP		0.92
MPC		0.63
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.50
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.74
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: chr11-108159829;