3-142503442-A-T

Variant names:

• chr3-142503442-A-T
• rs2227931
• NM_001184.4:c.5208T>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001184.4(ATR):​c.5208T>A​(p.Tyr1736*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y1736Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ATR NM_001184.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 1 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: 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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATR	NM_001184.4	MANE Select	c.5208T>A	p.Tyr1736*	stop_gained	Exon 30 of 47	NP_001175.2
	ATR	NM_001354579.2		c.5016T>A	p.Tyr1672*	stop_gained	Exon 29 of 46	NP_001341508.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATR	ENST00000350721.9	TSL:1 MANE Select	c.5208T>A	p.Tyr1736*	stop_gained	Exon 30 of 47	ENSP00000343741.4
	ATR	ENST00000936442.1		c.5055T>A	p.Tyr1685*	stop_gained	Exon 29 of 46	ENSP00000606501.1
	ATR	ENST00000661310.1		c.5016T>A	p.Tyr1672*	stop_gained	Exon 29 of 46	ENSP00000499589.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.94e-7 AC: 1 AN: 1440172 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 717398

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

African (AFR) AF: 0.00 AC: 0 AN: 33120

American (AMR) AF: 0.00 AC: 0 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.00 AC: 0 AN: 39488

South Asian (SAS) AF: 0.00 AC: 0 AN: 84870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1093972

Other (OTH) AF: 0.00 AC: 0 AN: 59610

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		1.3
Vest4		0.99
GERP RS		-0.052
Mutation Taster		=5/195	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs2227931; hg19: chr3-142222284;