rs28910273

Variant names:

• chr3-142469495-A-C
• rs28910273
• NM_001184.4:c.6394T>G

Your query was ambiguous. Multiple possible variants found:

• chr3-142469495-A-C
• chr3-142469495-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001184.4(ATR):​c.6394T>G​(p.Tyr2132Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00539 in 1,613,910 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y2132C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (24 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.40
• Publications: 17 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

ENSG00000244327 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008821011).
• BP6: Variant 3-142469495-A-C is Benign according to our data. Variant chr3-142469495-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0056 (8180/1461578) while in subpopulation NFE AF = 0.00684 (7608/1111820). AF 95% confidence interval is 0.00671. There are 24 homozygotes in GnomAdExome4. There are 3938 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 24 AR,AD,Unknown gene

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.6394T>G	p.Tyr2132Asp	missense	Exon 38 of 47	NP_001175.2	Q13535-1
	ATR	NM_001354579.2		c.6202T>G	p.Tyr2068Asp	missense	Exon 37 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.6394T>G	p.Tyr2132Asp	missense	Exon 38 of 47	ENSP00000343741.4	Q13535-1
	ATR	ENST00000513291.2	TSL:1	n.1578T>G		non_coding_transcript_exon	Exon 8 of 16
	ATR	ENST00000936442.1		c.6241T>G	p.Tyr2081Asp	missense	Exon 37 of 46	ENSP00000606501.1

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 519 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00606

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00315 AC: 792 AN: 251154 AF XY: 0.00309

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00558

Gnomad OTH exome AF: 0.00311

GnomAD4 exome AF: 0.00560 AC: 8180 AN: 1461578 Hom.: 24 Cov.: 31 AF XY: 0.00542 AC XY: 3938 AN XY: 727112

African (AFR) AF: 0.000897 AC: 30 AN: 33460

American (AMR) AF: 0.00177 AC: 79 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00144 AC: 124 AN: 86250

European-Finnish (FIN) AF: 0.000711 AC: 38 AN: 53410

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.00684 AC: 7608 AN: 1111820

Other (OTH) AF: 0.00490 AC: 296 AN: 60388

GnomAD4 genome AF: 0.00340 AC: 518 AN: 152332 Hom.: 0 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74484

African (AFR) AF: 0.00149 AC: 62 AN: 41590

American (AMR) AF: 0.00144 AC: 22 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00603 AC: 410 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00471 Hom.: 5

Bravo AF: 0.00348

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00686 AC: 59

ExAC AF: 0.00330 AC: 401

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00574

EpiControl AF: 0.00557

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not provided (9)
-	-	2	Seckel syndrome 1 (2)
-	-	1	ATR-related disorder (1)
-	-	1	Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Benign	0.63
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.71
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.2	N
PhyloP100		2.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.99	N
REVEL	Benign	0.048
Sift	Benign	0.062	T
Sift4G	Benign	0.076	T
Polyphen		0.0010	B
Vest4		0.27
MVP		0.23
MPC		1.1
ClinPred		0.0040	T
GERP RS		0.82
Varity_R		0.092
gMVP		0.26
Mutation Taster		=97/3	polymorphism

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: rs28910273; hg19: chr3-142188337; COSMIC: COSV63384218;