3-142459276-G-C

Variant names:

• chr3-142459276-G-C
• rs33972295
• NM_001184.4:c.7300C>G

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.7300C>G​(p.Pro2434Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00225 in 1,613,982 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (32 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (31 hom.)
• Consequence: ATR NM_001184.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 6.65
• Publications: 9 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

ENSG00000295506 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007993221).
• BP6: Variant 3-142459276-G-C is Benign according to our data. Variant chr3-142459276-G-C is described in ClinVar as Benign. ClinVar VariationId is 158003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1765/152286) while in subpopulation AFR AF = 0.041 (1703/41570). AF 95% confidence interval is 0.0393. There are 32 homozygotes in GnomAd4. There are 830 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 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.7300C>G	p.Pro2434Ala	missense	Exon 43 of 47	NP_001175.2
	ATR	NM_001354579.2		c.7108C>G	p.Pro2370Ala	missense	Exon 42 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.7300C>G	p.Pro2434Ala	missense	Exon 43 of 47	ENSP00000343741.4
	ATR	ENST00000513291.2	TSL:1	n.2484C>G		non_coding_transcript_exon	Exon 13 of 16
	ATR	ENST00000661310.1		c.7108C>G	p.Pro2370Ala	missense	Exon 42 of 46	ENSP00000499589.1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1764 AN: 152168 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00282

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00322 AC: 808 AN: 251314 AF XY: 0.00238

Gnomad AFR exome AF: 0.0430

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00128 AC: 1866 AN: 1461696 Hom.: 31 Cov.: 32 AF XY: 0.00112 AC XY: 813 AN XY: 727154

African (AFR) AF: 0.0431 AC: 1443 AN: 33476

American (AMR) AF: 0.00210 AC: 94 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86246

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.000130 AC: 144 AN: 1111870

Other (OTH) AF: 0.00260 AC: 157 AN: 60390

GnomAD4 genome AF: 0.0116 AC: 1765 AN: 152286 Hom.: 32 Cov.: 32 AF XY: 0.0111 AC XY: 830 AN XY: 74460

African (AFR) AF: 0.0410 AC: 1703 AN: 41570

American (AMR) AF: 0.00281 AC: 43 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68008

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00207 Hom.: 4

Bravo AF: 0.0139

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0386 AC: 170

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00382 AC: 464

Asia WGS AF: 0.00231 AC: 9 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.52
Sift	Benign	0.033	D
Sift4G	Benign	0.092	T
Polyphen		1.0	D
Vest4		0.51
MVP		0.78
MPC		0.69
ClinPred		0.095	T
GERP RS		3.7
Varity_R		0.63
gMVP		0.49
Mutation Taster		=74/26	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: rs33972295; hg19: chr3-142178118; COSMIC: COSV104670817;