3-142503442-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001184.4(ATR):​c.5208T>C​(p.Tyr1736Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 1,587,382 control chromosomes in the GnomAD database, including 120,773 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9419 hom., cov: 32)
  • Exomes 𝑓: 0.39 (111354 hom.)
• Consequence: ATR NM_001184.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.31
• Publications: 35 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 3-142503442-A-G is Benign according to our data. Variant chr3-142503442-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 157992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

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>C	p.Tyr1736Tyr	synonymous	Exon 30 of 47	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.5016T>C	p.Tyr1672Tyr	synonymous	Exon 29 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.5208T>C	p.Tyr1736Tyr	synonymous	Exon 30 of 47	ENSP00000343741.4	Q13535-1
	ATR	ENST00000936442.1		c.5055T>C	p.Tyr1685Tyr	synonymous	Exon 29 of 46	ENSP00000606501.1
	ATR	ENST00000661310.1		c.5016T>C	p.Tyr1672Tyr	synonymous	Exon 29 of 46	ENSP00000499589.1	Q13535-2

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51985 AN: 151962 Hom.: 9415 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.354

Gnomad ASJ AF: 0.450

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.381

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.369

GnomAD2 exomes AF: 0.360 AC: 89658 AN: 248974 AF XY: 0.362

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.318

Gnomad ASJ exome AF: 0.462

Gnomad EAS exome AF: 0.362

Gnomad FIN exome AF: 0.389

Gnomad NFE exome AF: 0.404

Gnomad OTH exome AF: 0.390

GnomAD4 exome AF: 0.389 AC: 558182 AN: 1435302 Hom.: 111354 Cov.: 28 AF XY: 0.387 AC XY: 276871 AN XY: 715200

African (AFR) AF: 0.194 AC: 6409 AN: 33048

American (AMR) AF: 0.321 AC: 14197 AN: 44240

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 11827 AN: 25850

East Asian (EAS) AF: 0.324 AC: 12771 AN: 39434

South Asian (SAS) AF: 0.261 AC: 22120 AN: 84678

European-Finnish (FIN) AF: 0.383 AC: 20336 AN: 53136

Middle Eastern (MID) AF: 0.392 AC: 2240 AN: 5716

European-Non Finnish (NFE) AF: 0.409 AC: 445663 AN: 1089766

Other (OTH) AF: 0.381 AC: 22619 AN: 59434

GnomAD4 genome AF: 0.342 AC: 52007 AN: 152080 Hom.: 9419 Cov.: 32 AF XY: 0.342 AC XY: 25397 AN XY: 74328

African (AFR) AF: 0.204 AC: 8459 AN: 41522

American (AMR) AF: 0.354 AC: 5403 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 1560 AN: 3470

East Asian (EAS) AF: 0.354 AC: 1830 AN: 5174

South Asian (SAS) AF: 0.272 AC: 1312 AN: 4828

European-Finnish (FIN) AF: 0.381 AC: 4016 AN: 10546

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27988 AN: 67960

Other (OTH) AF: 0.371 AC: 783 AN: 2108

Alfa AF: 0.381 Hom.: 26916

Bravo AF: 0.337

Asia WGS AF: 0.323 AC: 1119 AN: 3470

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (2)
-	-	2	Seckel syndrome 1 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	5.2
DANN	Benign	0.53
PhyloP100		1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2227931; hg19: chr3-142222284; COSMIC: COSV63386201; COSMIC: COSV63386201;