rs2372536

Variant names:

• chr2-215325297-C-G
• rs2372536
• NM_004044.7:c.347C>G

Variant summary

Our verdict is Benign. The variant received -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:5
• Conservation: PhyloP100: 6.03
• Publications: 126 publications found

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: Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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.347C>G	p.Thr116Ser	missense	Exon 5 of 16	NP_004035.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATIC	ENST00000236959.14	TSL:1 MANE Select	c.347C>G	p.Thr116Ser	missense	Exon 5 of 16	ENSP00000236959.9	P31939-1
	ATIC	ENST00000435675.5	TSL:2	c.344C>G	p.Thr115Ser	missense	Exon 4 of 15	ENSP00000415935.1	P31939-2
	ATIC	ENST00000957330.1		c.347C>G	p.Thr116Ser	missense	Exon 5 of 16	ENSP00000627389.1

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

GnomAD2 exomes AF: 0.325 AC: 81828 AN: 251410 AF XY: 0.338

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 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

African (AFR) AF: 0.0778 AC: 2602 AN: 33458

American (AMR) AF: 0.328 AC: 14672 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 9010 AN: 26098

East Asian (EAS) AF: 0.249 AC: 9885 AN: 39662

South Asian (SAS) AF: 0.473 AC: 40780 AN: 86174

European-Finnish (FIN) AF: 0.277 AC: 14792 AN: 53388

Middle Eastern (MID) AF: 0.335 AC: 1931 AN: 5764

European-Non Finnish (NFE) AF: 0.326 AC: 361190 AN: 1109396

Other (OTH) AF: 0.327 AC: 19713 AN: 60282

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

African (AFR) AF: 0.0917 AC: 3803 AN: 41492

American (AMR) AF: 0.301 AC: 4587 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1211 AN: 3468

East Asian (EAS) AF: 0.272 AC: 1405 AN: 5168

South Asian (SAS) AF: 0.472 AC: 2273 AN: 4818

European-Finnish (FIN) AF: 0.271 AC: 2841 AN: 10492

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.325 AC: 22105 AN: 67958

Other (OTH) AF: 0.281 AC: 594 AN: 2112

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	AICA-ribosiduria (2)
-	-	2	not provided (2)
-	-	1	ATIC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.0
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.32
Sift	Benign	0.13	T
Sift4G	Benign	0.33	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
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

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