NM_004044.7:c.-59T>G

Variant names:

• chr2-215312084-T-G
• rs4535042
• NM_004044.7:c.-59T>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.-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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.144
• Publications: 19 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

LOC124907975 (HGNC:):

ACMG classification

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 VariationId 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.

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.-59T>G		5_prime_UTR	Exon 1 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.-59T>G		5_prime_UTR	Exon 1 of 16	ENSP00000236959.9	P31939-1
	ATIC	ENST00000957330.1		c.-59T>G		5_prime_UTR	Exon 1 of 16	ENSP00000627389.1
	ATIC	ENST00000939851.1		c.-59T>G		5_prime_UTR	Exon 1 of 16	ENSP00000609910.1

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35377 AN: 152100 Hom.: 5126 Cov.: 34

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.: 33 AF XY: 0.308 AC XY: 209190 AN XY: 679094

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

GnomAD4 genome AF: 0.233 AC: 35393 AN: 152216 Hom.: 5130 Cov.: 34 AF XY: 0.235 AC XY: 17469 AN XY: 74440

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: 93 AN: 294

European-Non Finnish (NFE) AF: 0.302 AC: 20539 AN: 67970

Other (OTH) AF: 0.252 AC: 533 AN: 2114

Alfa AF: 0.145 Hom.: 295

Bravo AF: 0.224

Asia WGS AF: 0.368 AC: 1278 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	AICA-ribosiduria (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.9
DANN	Benign	0.58
PhyloP100		-0.14
PromoterAI		0.44	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4535042; hg19: chr2-216176807;