3-142555897-AT-ATT

Variant names:

• chr3-142555897-A-AT
• rs757500301
• NM_001184.4:c.2320dupA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001184.4(ATR):​c.2320dupA​(p.Ile774AsnfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000964 in 1,463,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (0 hom.)
• Consequence: ATR NM_001184.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.199
• Publications: 30 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 3-142555897-A-AT is Pathogenic according to our data. Variant chr3-142555897-A-AT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 938417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2320dupA	p.Ile774AsnfsTer3	frameshift	Exon 10 of 47	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.2128dupA	p.Ile710AsnfsTer3	frameshift	Exon 9 of 46	NP_001341508.1	Q13535-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATR	ENST00000350721.9	TSL:1 MANE Select	c.2320dupA	p.Ile774AsnfsTer3	frameshift	Exon 10 of 47	ENSP00000343741.4	Q13535-1
	ATR	ENST00000936442.1		c.2167dupA	p.Ile723AsnfsTer3	frameshift	Exon 9 of 46	ENSP00000606501.1
	ATR	ENST00000661310.1		c.2128dupA	p.Ile710AsnfsTer3	frameshift	Exon 9 of 46	ENSP00000499589.1	Q13535-2

Frequencies

GnomAD3 genomes AF: 0.0000399 AC: 6 AN: 150366 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000980

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000444

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00333 AC: 603 AN: 181094 AF XY: 0.00307

Gnomad AFR exome AF: 0.00219

Gnomad AMR exome AF: 0.00646

Gnomad ASJ exome AF: 0.00310

Gnomad EAS exome AF: 0.00310

Gnomad FIN exome AF: 0.00260

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00542

GnomAD4 exome AF: 0.00107 AC: 1404 AN: 1312876 Hom.: 0 Cov.: 31 AF XY: 0.00106 AC XY: 691 AN XY: 652768

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00196 AC: 58 AN: 29646

American (AMR) AF: 0.00368 AC: 144 AN: 39118

Ashkenazi Jewish (ASJ) AF: 0.00132 AC: 30 AN: 22722

East Asian (EAS) AF: 0.000930 AC: 33 AN: 35500

South Asian (SAS) AF: 0.00213 AC: 159 AN: 74488

European-Finnish (FIN) AF: 0.00114 AC: 54 AN: 47262

Middle Eastern (MID) AF: 0.000576 AC: 3 AN: 5206

European-Non Finnish (NFE) AF: 0.000858 AC: 862 AN: 1005134

Other (OTH) AF: 0.00113 AC: 61 AN: 53800

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000399 AC: 6 AN: 150366 Hom.: 0 Cov.: 32 AF XY: 0.0000409 AC XY: 3 AN XY: 73330

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000488 AC: 2 AN: 40962

American (AMR) AF: 0.00 AC: 0 AN: 15044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4768

European-Finnish (FIN) AF: 0.0000980 AC: 1 AN: 10204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.0000444 AC: 3 AN: 67498

Other (OTH) AF: 0.00 AC: 0 AN: 2064

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0182698), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0140 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome;C4551474:Seckel syndrome 1 (1)
1	-	-	Seckel syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs757500301; hg19: chr3-142274739; COSMIC: COSV63384207; COSMIC: COSV63384207;