Genetic Variant NM_004044.7:c.-59T>G (chr2-215312084-T-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004044.7(ATIC):c.-59T>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.295 in 1,528,280 control chromosomes in the GnomAD database, including 70,884 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 5130 hom., cov: 34)

Exomes 𝑓: 0.30 ( 65754 hom. )

Consequence

ATIC
NM_004044.7 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.144

Publications

19 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet

ATIC links:

LOC124907975 (HGNC:):

LOC124907975 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 2-215312084-T-G is Benign according to our data. Variant chr2-215312084-T-G is described in ClinVar as [Benign]. Clinvar id is 1192366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATIC	NM_004044.7 link	c.-59T>G		5_prime_UTR_variant	Exon 1 of 16	ENST00000236959.14	NP_004035.2	P31939-1V9HWH7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATIC	ENST00000236959.14 link	c.-59T>G		5_prime_UTR_variant	Exon 1 of 16	1	NM_004044.7	ENSP00000236959.9		P31939-1

Frequencies

GnomAD3 genomes

AF:

0.233

AC:

35377

AN:

152100

Hom.:

5126

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0559

Gnomad AMI

AF:

0.327

Gnomad AMR

AF:

0.282

Gnomad ASJ

AF:

0.319

Gnomad EAS

AF:

0.220

Gnomad SAS

AF:

0.454

Gnomad FIN

AF:

0.270

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.302

Gnomad OTH

AF:

0.248

GnomAD4 exome

AF:

0.302

AC:

415869

AN:

1376064

Hom.:

65754

Cov.:

AF XY:

0.308

AC XY:

209190

AN XY:

679094

show subpopulations

African (AFR)

AF:

0.0447

AC:

1375

AN:

30744

American (AMR)

AF:

0.304

AC:

10743

AN:

35316

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

7782

AN:

24910

East Asian (EAS)

AF:

0.172

AC:

6069

AN:

35208

South Asian (SAS)

AF:

0.459

AC:

35934

AN:

78222

European-Finnish (FIN)

AF:

0.277

AC:

9517

AN:

34300

Middle Eastern (MID)

AF:

0.308

AC:

1301

AN:

4228

European-Non Finnish (NFE)

AF:

0.303

AC:

325643

AN:

1075668

Other (OTH)

AF:

0.305

AC:

17505

AN:

57468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

14191

28383

42574

56766

70957

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.233

AC:

35393

AN:

152216

Hom.:

5130

Cov.:

AF XY:

0.235

AC XY:

17469

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0557

AC:

2318

AN:

41580

American (AMR)

AF:

0.282

AC:

4310

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.319

AC:

1109

AN:

3472

East Asian (EAS)

AF:

0.220

AC:

1137

AN:

5174

South Asian (SAS)

AF:

0.455

AC:

2197

AN:

4826

European-Finnish (FIN)

AF:

0.270

AC:

2859

AN:

10588

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.302

AC:

20539

AN:

67970

Other (OTH)

AF:

0.252

AC:

533

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1368

2736

4103

5471

6839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.145

Hom.:

295

Bravo

AF:

0.224

Asia WGS

AF:

0.368

AC:

1278

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

AICA-ribosiduria

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

4.9

(source)

DANN

Benign

0.58

PhyloP100

-0.14

PromoterAI

0.44

Neutral

(source)

Mutation Taster

=300/0

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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NM_004044.7:c.-59T>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over