Genetic Variant ATR:c.7041+8G>T (chr3-142465089-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001184.4(ATR):c.7041+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000745 in 1,341,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

ATR
NM_001184.4 splice_region, intron

Scores

Splicing: ADA: 0.003029

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0940

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: G2P, Ambry Genetics, Illumina
familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome
Inheritance: AD, Unknown Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATR	NM_001184.4	MANE Select	c.7041+8G>T		splice_region intron	N/A	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.6849+8G>T		splice_region intron	N/A	NP_001341508.1	Q13535-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATR	ENST00000350721.9	TSL:1 MANE Select	c.7041+8G>T	splice_region intron	N/A	ENSP00000343741.4	Q13535-1
ATR	ENST00000513291.2	TSL:1	n.2225+8G>T	splice_region intron	N/A
ATR	ENST00000936442.1		c.6888+8G>T	splice_region intron	N/A	ENSP00000606501.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.45e-7

AC:

AN:

1341646

Hom.:

Cov.:

AF XY:

0.00000151

AC XY:

AN XY:

663512

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29694

American (AMR)

AF:

0.00

AC:

AN:

34280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23084

East Asian (EAS)

AF:

0.00

AC:

AN:

36276

South Asian (SAS)

AF:

0.00

AC:

AN:

60268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48440

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4798

European-Non Finnish (NFE)

AF:

9.52e-7

AC:

AN:

1050044

Other (OTH)

AF:

0.00

AC:

AN:

54762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.3

(source)

DANN

Benign

0.67

PhyloP100

0.094

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0030

dbscSNV1_RF

Benign

0.25

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over