NM_001184.4:c.632T>C

Variant names:

• chr3-142562770-A-G
• rs2227928
• NM_001184.4:c.632T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001184.4(ATR):​c.632T>C​(p.Met211Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,609,006 control chromosomes in the GnomAD database, including 272,275 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M211K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.63 (30706 hom., cov: 32)
  • Exomes 𝑓: 0.57 (241569 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.48
• Publications: 92 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=8.809924E-7).
• BP6: Variant 3-142562770-A-G is Benign according to our data. Variant chr3-142562770-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

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.632T>C	p.Met211Thr	missense	Exon 4 of 47	NP_001175.2
	ATR	NM_001354579.2		c.632T>C	p.Met211Thr	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.632T>C	p.Met211Thr	missense	Exon 4 of 47	ENSP00000343741.4
	ATR	ENST00000936442.1		c.632T>C	p.Met211Thr	missense	Exon 4 of 46	ENSP00000606501.1
	ATR	ENST00000661310.1		c.632T>C	p.Met211Thr	missense	Exon 4 of 46	ENSP00000499589.1

Frequencies

GnomAD3 genomes AF: 0.625 AC: 95022 AN: 151920 Hom.: 30655 Cov.: 32

Gnomad AFR AF: 0.790

Gnomad AMI AF: 0.679

Gnomad AMR AF: 0.534

Gnomad ASJ AF: 0.560

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.621

GnomAD2 exomes AF: 0.548 AC: 135126 AN: 246404 AF XY: 0.544

Gnomad AFR exome AF: 0.797

Gnomad AMR exome AF: 0.456

Gnomad ASJ exome AF: 0.567

Gnomad EAS exome AF: 0.470

Gnomad FIN exome AF: 0.552

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.555

GnomAD4 exome AF: 0.572 AC: 833938 AN: 1456968 Hom.: 241569 Cov.: 55 AF XY: 0.568 AC XY: 411764 AN XY: 724462

African (AFR) AF: 0.802 AC: 26595 AN: 33170

American (AMR) AF: 0.464 AC: 20207 AN: 43556

Ashkenazi Jewish (ASJ) AF: 0.562 AC: 14554 AN: 25916

East Asian (EAS) AF: 0.444 AC: 17630 AN: 39670

South Asian (SAS) AF: 0.435 AC: 36925 AN: 84936

European-Finnish (FIN) AF: 0.548 AC: 29225 AN: 53328

Middle Eastern (MID) AF: 0.564 AC: 3237 AN: 5742

European-Non Finnish (NFE) AF: 0.586 AC: 650978 AN: 1110492

Other (OTH) AF: 0.575 AC: 34587 AN: 60158

GnomAD4 genome AF: 0.626 AC: 95120 AN: 152038 Hom.: 30706 Cov.: 32 AF XY: 0.618 AC XY: 45903 AN XY: 74320

African (AFR) AF: 0.791 AC: 32790 AN: 41470

American (AMR) AF: 0.534 AC: 8152 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.560 AC: 1943 AN: 3468

East Asian (EAS) AF: 0.464 AC: 2397 AN: 5162

South Asian (SAS) AF: 0.443 AC: 2138 AN: 4826

European-Finnish (FIN) AF: 0.539 AC: 5692 AN: 10566

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.587 AC: 39898 AN: 67962

Other (OTH) AF: 0.625 AC: 1314 AN: 2102

Alfa AF: 0.591 Hom.: 106946

Bravo AF: 0.633

TwinsUK AF: 0.598 AC: 2217

ALSPAC AF: 0.579 AC: 2232

ESP6500AA AF: 0.793 AC: 3493

ESP6500EA AF: 0.595 AC: 5121

ExAC AF: 0.552 AC: 67071

Asia WGS AF: 0.506 AC: 1760 AN: 3478

EpiCase AF: 0.590

EpiControl AF: 0.588

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	10
DANN	Benign	0.59
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.037	T
MetaRNN	Benign	8.8e-7	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.14	N
PhyloP100		1.5
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.089
Sift	Benign	1.0	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.18
ClinPred		0.0013	T
GERP RS		4.6
Varity_R		0.081
gMVP		0.20
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: rs2227928; hg19: chr3-142281612; COSMIC: COSV63383325; COSMIC: COSV63383325;