rs1553770633

Variant names:

• chr3-142556126-C-T
• rs1553770633
• NM_001184.4:c.2092G>A

Your query was ambiguous. Multiple possible variants found:

• chr3-142556126-C-T
• chr3-142556126-C-A
• chr3-142556126-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001184.4(ATR):​c.2092G>A​(p.Asp698Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,306 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. D698D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.82
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• 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.2092G>A	p.Asp698Asn	missense	Exon 10 of 47	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.1900G>A	p.Asp634Asn	missense	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.2092G>A	p.Asp698Asn	missense	Exon 10 of 47	ENSP00000343741.4	Q13535-1
	ATR	ENST00000936442.1		c.1939G>A	p.Asp647Asn	missense	Exon 9 of 46	ENSP00000606501.1
	ATR	ENST00000661310.1		c.1900G>A	p.Asp634Asn	missense	Exon 9 of 46	ENSP00000499589.1	Q13535-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461200 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726848

African (AFR) AF: 0.0000299 AC: 1 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.00 AC: 0 AN: 85996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111788

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

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

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.0000655 AC: 1 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	not specified (1)
-	1	-	Seckel syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.077	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.8	L
PhyloP100		5.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.23
Sift	Uncertain	0.019	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.36		Gain of glycosylation at S700 (P = 0.0468)
MVP		0.73
MPC		0.67
ClinPred		0.93	D
GERP RS		4.8
Varity_R		0.38
gMVP		0.32
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1553770633; hg19: chr3-142274968;