chr2-215325296-A-T

Variant names:

• chr2-215325296-A-T
• NM_004044.7:c.346A>T
• ATIC p.Thr116Ser

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004044.7(ATIC):​c.346A>T​(p.Thr116Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ATIC NM_004044.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.36
• Publications: 0 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, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31458497).

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.346A>T	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.346A>T	p.Thr116Ser	missense	Exon 5 of 16	ENSP00000236959.9	P31939-1
	ATIC	ENST00000435675.5	TSL:2	c.343A>T	p.Thr115Ser	missense	Exon 4 of 15	ENSP00000415935.1	P31939-2
	ATIC	ENST00000957330.1		c.346A>T	p.Thr116Ser	missense	Exon 5 of 16	ENSP00000627389.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.13
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.4
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.28
Sift	Benign	0.13	T
Sift4G	Benign	0.33	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.53
Mutation Taster		=49/51	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr2-216190019;