3-142562456-C-T

Variant names:

• chr3-142562456-C-T
• rs28897764
• NM_001184.4:c.946G>A

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.946G>A​(p.Val316Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,614,050 control chromosomes in the GnomAD database, including 399 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V316L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (29 hom., cov: 33)
  • Exomes 𝑓: 0.020 (370 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.07
• Publications: 27 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006286353).
• BP6: Variant 3-142562456-C-T is Benign according to our data. Variant chr3-142562456-C-T is described in ClinVar as Benign. ClinVar VariationId is 158006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0178 (2712/152268) while in subpopulation SAS AF = 0.0411 (198/4818). AF 95% confidence interval is 0.0364. There are 29 homozygotes in GnomAd4. There are 1275 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 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.946G>A	p.Val316Ile	missense	Exon 4 of 47	NP_001175.2
	ATR	NM_001354579.2		c.946G>A	p.Val316Ile	missense	Exon 4 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.946G>A	p.Val316Ile	missense	Exon 4 of 47	ENSP00000343741.4
	ATR	ENST00000936442.1		c.946G>A	p.Val316Ile	missense	Exon 4 of 46	ENSP00000606501.1
	ATR	ENST00000661310.1		c.946G>A	p.Val316Ile	missense	Exon 4 of 46	ENSP00000499589.1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2712 AN: 152150 Hom.: 29 Cov.: 33

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0415

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0184

Gnomad OTH AF: 0.0186

GnomAD2 exomes AF: 0.0181 AC: 4559 AN: 251222 AF XY: 0.0196

Gnomad AFR exome AF: 0.0186

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0296

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00360

Gnomad NFE exome AF: 0.0183

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0198 AC: 28998 AN: 1461782 Hom.: 370 Cov.: 30 AF XY: 0.0204 AC XY: 14848 AN XY: 727188

African (AFR) AF: 0.0200 AC: 670 AN: 33476

American (AMR) AF: 0.0113 AC: 507 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0307 AC: 802 AN: 26130

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39690

South Asian (SAS) AF: 0.0412 AC: 3555 AN: 86254

European-Finnish (FIN) AF: 0.00376 AC: 201 AN: 53418

Middle Eastern (MID) AF: 0.0380 AC: 219 AN: 5768

European-Non Finnish (NFE) AF: 0.0195 AC: 21668 AN: 1111928

Other (OTH) AF: 0.0227 AC: 1370 AN: 60394

GnomAD4 genome AF: 0.0178 AC: 2712 AN: 152268 Hom.: 29 Cov.: 33 AF XY: 0.0171 AC XY: 1275 AN XY: 74450

African (AFR) AF: 0.0211 AC: 877 AN: 41542

American (AMR) AF: 0.0127 AC: 194 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 113 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0411 AC: 198 AN: 4818

European-Finnish (FIN) AF: 0.00283 AC: 30 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0184 AC: 1255 AN: 68026

Other (OTH) AF: 0.0184 AC: 39 AN: 2116

Alfa AF: 0.0186 Hom.: 99

Bravo AF: 0.0179

TwinsUK AF: 0.0221 AC: 82

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.0200 AC: 172

ExAC AF: 0.0189 AC: 2290

Asia WGS AF: 0.0270 AC: 94 AN: 3478

EpiCase AF: 0.0224

EpiControl AF: 0.0200

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	3	Seckel syndrome 1 (3)
-	-	2	Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.054
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.1
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.034
Sift	Benign	0.24	T
Sift4G	Benign	0.33	T
Polyphen		0.022	B
Vest4		0.043
MPC		0.14
ClinPred		0.0072	T
GERP RS		4.4
Varity_R		0.050
gMVP		0.15
Mutation Taster		=99/1	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: rs28897764; hg19: chr3-142281298; COSMIC: COSV63385678;