Variant rs377689383 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001184.4(ATR):c.3799G>C(p.Val1267Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,432,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. V1267I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ATR
NM_001184.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.25

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATR. . Gene score misZ 4.3648 (greater than the threshold 3.09). Trascript score misZ 7.1274 (greater than threshold 3.09). GenCC has associacion of gene with sarcoma, Seckel syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Seckel syndrome 1.

BP4

Computational evidence support a benign effect (MetaRNN=0.21703622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATR	NM_001184.4 linkuse as main transcript	c.3799G>C	p.Val1267Leu	missense_variant	20/47	ENST00000350721.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATR	ENST00000350721.9 linkuse as main transcript	c.3799G>C	p.Val1267Leu	missense_variant	20/47	1	NM_001184.4	P1	Q13535-1
ATR	ENST00000661310.1 linkuse as main transcript	c.3607G>C	p.Val1203Leu	missense_variant	19/46				Q13535-2
ATR	ENST00000653868.1 linkuse as main transcript	n.3828G>C		non_coding_transcript_exon_variant	20/35
ATR	ENST00000656590.1 linkuse as main transcript	c.2590G>C	p.Val864Leu	missense_variant, NMD_transcript_variant	16/44

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249780

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135390

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1432150

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000184

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

7.9

DANN

Benign

0.96

DEOGEN2

Benign

0.12

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.024

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.83

MutationAssessor

Benign

2.0

MutationTaster

Benign

0.97

D;D

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.0

REVEL

Benign

0.16

Sift

Benign

0.14

Sift4G

Benign

0.22

Polyphen

0.020

Vest4

0.47

MutPred

0.41

Gain of glycosylation at Y1271 (P = 0.0387);

MVP

0.52

MPC

0.67

ClinPred

0.093

GERP RS

2.5

Varity_R

0.093

gMVP

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over