Genetic Variant ATR:p.Arg2425Pro (chr3-142459302-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001184.4(ATR):c.7274G>C(p.Arg2425Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 in silico tools predict a benign outcome for this variant. 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. R2425Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

ATR
NM_001184.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0370

Publications

0 publications found

Variant links:

Genes affected

ATR (HGNC:882): (ATR serine/threonine kinase) The protein encoded by this gene is a serine/threonine kinase and DNA damage sensor, activating cell cycle checkpoint signaling upon DNA stress. The encoded protein can phosphorylate and activate several proteins involved in the inhibition of DNA replication and mitosis, and can promote DNA repair, recombination, and apoptosis. This protein is also important for fragile site stability and centrosome duplication. Defects in this gene are a cause of Seckel syndrome 1. [provided by RefSeq, Aug 2017]

ATR Gene-Disease associations (from GenCC):

Seckel syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Ambry Genetics
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome
Inheritance: Unknown, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
Seckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
familial prostate carcinoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ATR links:

ENSG00000295506 (HGNC:):

ENSG00000295506 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001184.4. 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
	ATR	NM_001184.4	MANE Select	c.7274G>C	p.Arg2425Pro	missense	Exon 43 of 47	NP_001175.2
	ATR	NM_001354579.2		c.7082G>C	p.Arg2361Pro	missense	Exon 42 of 46	NP_001341508.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ATR	ENST00000350721.9	TSL:1 MANE Select	c.7274G>C	p.Arg2425Pro	missense	Exon 43 of 47	ENSP00000343741.4
ATR	ENST00000513291.2	TSL:1	n.2458G>C		non_coding_transcript_exon	Exon 13 of 16
ATR	ENST00000661310.1		c.7082G>C	p.Arg2361Pro	missense	Exon 42 of 46	ENSP00000499589.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Benign

-0.26

CADD

Benign

5.8

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.17

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.85

M_CAP

Benign

0.065

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.5

PhyloP100

0.037

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.46

Sift

Benign

0.19

Sift4G

Benign

0.11

Polyphen

0.18

Vest4

0.40

MutPred

0.64

Gain of ubiquitination at K2420 (P = 0.0442)

MVP

0.79

MPC

1.1

ClinPred

0.23

GERP RS

-9.1

Varity_R

0.77

gMVP

0.81

Mutation Taster

=59/41

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over