Genetic Variant ATIC:c.380-56C>T (chr2-215325931-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004044.7(ATIC):c.380-56C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,580,358 control chromosomes in the GnomAD database, including 165,880 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.46 ( 16533 hom., cov: 32)

Exomes 𝑓: 0.45 ( 149347 hom. )

Consequence

ATIC
NM_004044.7 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.467

Publications

28 publications found

Variant links:

Genes affected

ATIC (HGNC:794): (5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase) This gene encodes a bifunctional protein that catalyzes the last two steps of the de novo purine biosynthetic pathway. The N-terminal domain has phosphoribosylaminoimidazolecarboxamide formyltransferase activity, and the C-terminal domain has IMP cyclohydrolase activity. A mutation in this gene results in AICA-ribosiduria. [provided by RefSeq, Sep 2009]

ATIC Gene-Disease associations (from GenCC):

AICA-ribosiduria
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ATIC links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.502 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004044.7. 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
	ATIC	NM_004044.7	MANE Select	c.380-56C>T		intron	N/A	NP_004035.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ATIC	ENST00000236959.14	TSL:1 MANE Select	c.380-56C>T	intron	N/A	ENSP00000236959.9	P31939-1
ATIC	ENST00000435675.5	TSL:2	c.377-56C>T	intron	N/A	ENSP00000415935.1	P31939-2
ATIC	ENST00000957330.1		c.380-56C>T	intron	N/A	ENSP00000627389.1

Frequencies

GnomAD3 genomes

AF:

0.462

AC:

70133

AN:

151914

Hom.:

16523

Cov.:

show subpopulations

Gnomad AFR

AF:

0.508

Gnomad AMI

AF:

0.461

Gnomad AMR

AF:

0.418

Gnomad ASJ

AF:

0.411

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.323

Gnomad FIN

AF:

0.491

Gnomad MID

AF:

0.427

Gnomad NFE

AF:

0.470

Gnomad OTH

AF:

0.459

GnomAD4 exome

AF:

0.453

AC:

647664

AN:

1428326

Hom.:

149347

AF XY:

0.449

AC XY:

319744

AN XY:

712386

show subpopulations

African (AFR)

AF:

0.517

AC:

16859

AN:

32608

American (AMR)

AF:

0.358

AC:

15857

AN:

44346

Ashkenazi Jewish (ASJ)

AF:

0.414

AC:

10707

AN:

25854

East Asian (EAS)

AF:

0.274

AC:

10783

AN:

39304

South Asian (SAS)

AF:

0.313

AC:

26629

AN:

85092

European-Finnish (FIN)

AF:

0.481

AC:

25459

AN:

52918

Middle Eastern (MID)

AF:

0.425

AC:

2423

AN:

5704

European-Non Finnish (NFE)

AF:

0.474

AC:

513391

AN:

1083308

Other (OTH)

AF:

0.432

AC:

25556

AN:

59192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

17664

35329

52993

70658

88322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15038

30076

45114

60152

75190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.462

AC:

70164

AN:

152032

Hom.:

16533

Cov.:

AF XY:

0.459

AC XY:

34097

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.508

AC:

21040

AN:

41440

American (AMR)

AF:

0.418

AC:

6383

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.411

AC:

1425

AN:

3470

East Asian (EAS)

AF:

0.222

AC:

1146

AN:

5166

South Asian (SAS)

AF:

0.321

AC:

1549

AN:

4820

European-Finnish (FIN)

AF:

0.491

AC:

5189

AN:

10564

Middle Eastern (MID)

AF:

0.439

AC:

129

AN:

294

European-Non Finnish (NFE)

AF:

0.470

AC:

31926

AN:

67976

Other (OTH)

AF:

0.455

AC:

960

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1959

3918

5877

7836

9795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

636

1272

1908

2544

3180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.463

Hom.:

11770

Bravo

AF:

0.457

Asia WGS

AF:

0.278

AC:

970

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.39

(source)

DANN

Benign

0.63

PhyloP100

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over