NM_001184.4:c.632T>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001184.4(ATR):​c.632T>G​(p.Met211Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M211T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12454784).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATR	NM_001184.4	c.632T>G	p.Met211Arg	missense_variant	Exon 4 of 47	ENST00000350721.9	NP_001175.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATR	ENST00000350721.9	c.632T>G	p.Met211Arg	missense_variant	Exon 4 of 47	1	NM_001184.4	ENSP00000343741.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.14	N
PhyloP100		1.5
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.42	N
REVEL	Benign	0.066
Sift	Benign	0.15	T
Sift4G	Benign	0.49	T
Polyphen		0.0	B
Vest4		0.26
MutPred		0.57		Gain of MoRF binding (P = 0.0206);
MVP		0.43
MPC		0.24
ClinPred		0.048	T
GERP RS		4.6
Varity_R		0.24
gMVP		0.50
Mutation Taster		=99/1	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: rs2227928; hg19: chr3-142281612;