rs77208665

Variant names:

• chr3-142555928-T-C
• rs77208665
• NM_001184.4:c.2290A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001184.4(ATR):​c.2290A>G​(p.Lys764Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00459 in 1,612,994 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. K764K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (30 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 4.14
• Publications: 16 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009344518).
• BP6: Variant 3-142555928-T-C is Benign according to our data. Variant chr3-142555928-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 157970.
• BS2: High Homozygotes in GnomAd4 at 2 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.2290A>G	p.Lys764Glu	missense	Exon 10 of 47	NP_001175.2
	ATR	NM_001354579.2		c.2098A>G	p.Lys700Glu	missense	Exon 9 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.2290A>G	p.Lys764Glu	missense	Exon 10 of 47	ENSP00000343741.4
	ATR	ENST00000936442.1		c.2137A>G	p.Lys713Glu	missense	Exon 9 of 46	ENSP00000606501.1
	ATR	ENST00000661310.1		c.2098A>G	p.Lys700Glu	missense	Exon 9 of 46	ENSP00000499589.1

Frequencies

GnomAD3 genomes AF: 0.00337 AC: 513 AN: 152172 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00507

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00329 AC: 823 AN: 250116 AF XY: 0.00317

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00253

Gnomad ASJ exome AF: 0.00628

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00498

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00472 AC: 6889 AN: 1460704 Hom.: 30 Cov.: 31 AF XY: 0.00445 AC XY: 3233 AN XY: 726554

African (AFR) AF: 0.000599 AC: 20 AN: 33384

American (AMR) AF: 0.00234 AC: 104 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.00670 AC: 175 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.000769 AC: 66 AN: 85800

European-Finnish (FIN) AF: 0.00210 AC: 112 AN: 53410

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5758

European-Non Finnish (NFE) AF: 0.00542 AC: 6021 AN: 1111706

Other (OTH) AF: 0.00618 AC: 373 AN: 60344

GnomAD4 genome AF: 0.00337 AC: 513 AN: 152290 Hom.: 2 Cov.: 32 AF XY: 0.00340 AC XY: 253 AN XY: 74466

African (AFR) AF: 0.000674 AC: 28 AN: 41566

American (AMR) AF: 0.00608 AC: 93 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00519 AC: 18 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10612

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00507 AC: 345 AN: 68030

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00449 Hom.: 10

Bravo AF: 0.00351

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00325 AC: 395

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.00567

EpiControl AF: 0.00551

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	1	1	Seckel syndrome 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.031
Eigen_PC	Benign	0.0053
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0093	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.1
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.21
Sift	Benign	0.042	D
Sift4G	Uncertain	0.021	D
Polyphen		0.92	P
Vest4		0.62
MVP		0.79
MPC		0.53
ClinPred		0.011	T
GERP RS		4.2
Varity_R		0.36
gMVP		0.34
Mutation Taster		=98/2	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: rs77208665; hg19: chr3-142274770; COSMIC: COSV63389180;