Genetic Variant ATIC:c.19+94G>A (chr2-215312255-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_004044.7(ATIC):c.19+94G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00929 in 1,457,288 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0077 ( 13 hom., cov: 33)

Exomes 𝑓: 0.0095 ( 97 hom. )

Consequence

ATIC
NM_004044.7 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.40

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 2-215312255-G-A is Benign according to our data. Variant chr2-215312255-G-A is described in ClinVar as [Benign]. Clinvar id is 2651868.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00948 (12376/1305028) while in subpopulation MID AF = 0.0435 (162/3726). AF 95% confidence interval is 0.038. There are 97 homozygotes in GnomAdExome4. There are 6195 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATIC	NM_004044.7 link	c.19+94G>A		intron_variant	Intron 1 of 15	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.19+94G>A		intron_variant	Intron 1 of 15	1	NM_004044.7	ENSP00000236959.9		P31939-1

Frequencies

GnomAD3 genomes

AF:

0.00771

AC:

1173

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.0432

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0573

Gnomad NFE

AF:

0.00956

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0114

AC:

755

AN:

66442

AF XY:

0.0124

show subpopulations

Gnomad AFR exome

AF:

0.00327

Gnomad AMR exome

AF:

0.0133

Gnomad ASJ exome

AF:

0.0677

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00150

Gnomad NFE exome

AF:

0.0127

Gnomad OTH exome

AF:

0.00994

GnomAD4 exome

AF:

0.00948

AC:

12376

AN:

1305028

Hom.:

Cov.:

AF XY:

0.00969

AC XY:

6195

AN XY:

639524

show subpopulations

African (AFR)

AF:

0.00199

AC:

AN:

28586

American (AMR)

AF:

0.0124

AC:

284

AN:

22816

Ashkenazi Jewish (ASJ)

AF:

0.0469

AC:

928

AN:

19784

East Asian (EAS)

AF:

0.0000287

AC:

AN:

34880

South Asian (SAS)

AF:

0.00542

AC:

357

AN:

65830

European-Finnish (FIN)

AF:

0.00259

AC:

AN:

31248

Middle Eastern (MID)

AF:

0.0435

AC:

162

AN:

3726

European-Non Finnish (NFE)

AF:

0.00941

AC:

9824

AN:

1043770

Other (OTH)

AF:

0.0125

AC:

682

AN:

54388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

673

1346

2019

2692

3365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00768

AC:

1169

AN:

152260

Hom.:

Cov.:

AF XY:

0.00763

AC XY:

568

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00178

AC:

AN:

41572

American (AMR)

AF:

0.0137

AC:

209

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0432

AC:

150

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00373

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0514

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00955

AC:

649

AN:

67986

Other (OTH)

AF:

0.0175

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

124

187

249

311

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00257

Hom.:

Bravo

AF:

0.00869

Asia WGS

AF:

0.00231

AC:

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ATIC: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

3.9

(source)

DANN

Benign

0.92

PhyloP100

-2.4

PromoterAI

-0.042

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(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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2-215312255-G-A

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