NM_001184.4:c.268C>T

Variant names:

• chr3-142566145-G-A
• rs28897763
• NM_001184.4:c.268C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001184.4(ATR):​c.268C>T​(p.His90Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00605 in 1,614,130 control chromosomes in the GnomAD database, including 142 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H90H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0077 (19 hom., cov: 31)
  • Exomes 𝑓: 0.0059 (123 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.01
• Publications: 22 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00195992).
• BP6: Variant 3-142566145-G-A is Benign according to our data. Variant chr3-142566145-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 19 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATR	NM_001184.4	MANE Select	c.268C>T	p.His90Tyr	missense	Exon 3 of 47	NP_001175.2
	ATR	NM_001354579.2		c.268C>T	p.His90Tyr	missense	Exon 3 of 46	NP_001341508.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATR	ENST00000350721.9	TSL:1 MANE Select	c.268C>T	p.His90Tyr	missense	Exon 3 of 47	ENSP00000343741.4
	ATR	ENST00000661310.1		c.268C>T	p.His90Tyr	missense	Exon 3 of 46	ENSP00000499589.1
	ATR	ENST00000507148.1	TSL:3	n.268C>T		non_coding_transcript_exon	Exon 3 of 6	ENSP00000426595.1

Frequencies

GnomAD3 genomes AF: 0.00766 AC: 1165 AN: 152154 Hom.: 19 Cov.: 31

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0639

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00642

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00847 AC: 2130 AN: 251486 AF XY: 0.00821

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0595

Gnomad NFE exome AF: 0.00670

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00588 AC: 8601 AN: 1461858 Hom.: 123 Cov.: 31 AF XY: 0.00585 AC XY: 4251 AN XY: 727238

African (AFR) AF: 0.000687 AC: 23 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 29 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.0549 AC: 2935 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00480 AC: 5335 AN: 1111992

Other (OTH) AF: 0.00417 AC: 252 AN: 60396

GnomAD4 genome AF: 0.00765 AC: 1165 AN: 152272 Hom.: 19 Cov.: 31 AF XY: 0.00994 AC XY: 740 AN XY: 74438

African (AFR) AF: 0.000818 AC: 34 AN: 41560

American (AMR) AF: 0.000653 AC: 10 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.0639 AC: 677 AN: 10592

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

European-Non Finnish (NFE) AF: 0.00642 AC: 437 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00528 Hom.: 8

Bravo AF: 0.00277

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00757 AC: 919

EpiCase AF: 0.00622

EpiControl AF: 0.00480

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	Seckel syndrome 1 (2)
-	-	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	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.0
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.12
Sift	Benign	0.10	T
Sift4G	Benign	0.066	T
Polyphen		0.031	B
Vest4		0.28
MVP		0.41
MPC		0.20
ClinPred		0.0069	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.079
gMVP		0.063
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28897763; hg19: chr3-142284987; COSMIC: COSV63387997; COSMIC: COSV63387997;