rs2372536

chr2-215325297-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004044.7(ATIC):c.347C>G(p.Thr116Ser) variant causes a missense change. The variant allele was found at a frequency of 0.319 in 1,610,906 control chromosomes in the GnomAD database, including 86,062 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6016 hom., cov: 32)
  • Exomes 𝑓: 0.33 (80046 hom.)
• Consequence: ATIC NM_004044.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.03

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017181039).
• BP6: Variant 2-215325297-C-G is Benign according to our data. Variant chr2-215325297-C-G is described in ClinVar as [Benign]. Clinvar id is 801893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATIC	NM_004044.7	c.347C>G	p.Thr116Ser	missense_variant	5/16	ENST00000236959.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATIC	ENST00000236959.14	c.347C>G	p.Thr116Ser	missense_variant	5/16	1	NM_004044.7	P1

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39259 AN: 151858 Hom.: 6007 Cov.: 32

Gnomad AFR AF: 0.0915

Gnomad AMI AF: 0.415

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.272

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.278

GnomAD3 exomes AF: 0.325 AC: 81828 AN: 251410 Hom.: 14359 AF XY: 0.338 AC XY: 45939 AN XY: 135882

Gnomad AFR exome AF: 0.0877

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.294

Gnomad SAS exome AF: 0.477

Gnomad FIN exome AF: 0.277

Gnomad NFE exome AF: 0.329

Gnomad OTH exome AF: 0.318

GnomAD4 exome AF: 0.325 AC: 474575 AN: 1458932 Hom.: 80046 Cov.: 33 AF XY: 0.331 AC XY: 240355 AN XY: 725936

Gnomad4 AFR exome AF: 0.0778

Gnomad4 AMR exome AF: 0.328

Gnomad4 ASJ exome AF: 0.345

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.473

Gnomad4 FIN exome AF: 0.277

Gnomad4 NFE exome AF: 0.326

Gnomad4 OTH exome AF: 0.327

GnomAD4 genome AF: 0.259 AC: 39289 AN: 151974 Hom.: 6016 Cov.: 32 AF XY: 0.259 AC XY: 19235 AN XY: 74282

Gnomad4 AFR AF: 0.0917

Gnomad4 AMR AF: 0.301

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.272

Gnomad4 SAS AF: 0.472

Gnomad4 FIN AF: 0.271

Gnomad4 NFE AF: 0.325

Gnomad4 OTH AF: 0.281

Alfa AF: 0.313 Hom.: 2565

Bravo AF: 0.253

TwinsUK AF: 0.325 AC: 1205

ALSPAC AF: 0.328 AC: 1263

ESP6500AA AF: 0.0962 AC: 424

ESP6500EA AF: 0.324 AC: 2786

ExAC AF: 0.323 AC: 39268

Asia WGS AF: 0.388 AC: 1346 AN: 3478

EpiCase AF: 0.338

EpiControl AF: 0.334

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

AICA-ribosiduria Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

ATIC-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.50	D;.;.
Eigen	Benign	0.028
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.57	T;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.;.
MutationTaster	Benign	1.6e-9	P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.0010	B;.;.
Vest4		0.11
MutPred		0.24		Gain of disorder (P = 0.0286);.;.;
MPC		0.050
ClinPred		0.033	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2372536; hg19: chr2-216190020; COSMIC: COSV52691660;