NM_001330701.2:c.3337T>G

Variant names:

• chr9-85578925-A-C
• NM_001330701.2:c.3337T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001330701.2(AGTPBP1):​c.3337T>G​(p.Tyr1113Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: AGTPBP1 NM_001330701.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29
• Publications: 0 publications found

Genes affected

AGTPBP1 (HGNC:17258): (ATP/GTP binding carboxypeptidase 1) NNA1 is a zinc carboxypeptidase that contains nuclear localization signals and an ATP/GTP-binding motif that was initially cloned from regenerating spinal cord neurons of the mouse.[supplied by OMIM, Jul 2002]

AGTPBP1 Gene-Disease associations (from GenCC):

• neurodegeneration, childhood-onset, with cerebellar atrophy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330701.2. 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
	AGTPBP1	NM_001330701.2	MANE Select	c.3337T>G	p.Tyr1113Asp	missense	Exon 24 of 26	NP_001317630.1	Q9UPW5-1
	AGTPBP1	NM_001286715.1		c.3493T>G	p.Tyr1165Asp	missense	Exon 23 of 25	NP_001273644.1	J3KNS1
	AGTPBP1	NM_001286717.1		c.3373T>G	p.Tyr1125Asp	missense	Exon 23 of 25	NP_001273646.1	Q9UPW5-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTPBP1	ENST00000357081.8	TSL:5 MANE Select	c.3337T>G	p.Tyr1113Asp	missense	Exon 24 of 26	ENSP00000349592.3	Q9UPW5-1
	AGTPBP1	ENST00000376083.7	TSL:1	c.3217T>G	p.Tyr1073Asp	missense	Exon 24 of 26	ENSP00000365251.3	Q9UPW5-2
	AGTPBP1	ENST00000337006.8	TSL:5	c.3493T>G	p.Tyr1165Asp	missense	Exon 23 of 25	ENSP00000338512.5	J3KNS1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460336 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726496

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39492

South Asian (SAS) AF: 0.00 AC: 0 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111438

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.085	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.3	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.83
MutPred		0.54		Gain of sheet (P = 4e-04)
MVP		0.49
MPC		0.37
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.88
gMVP		0.79
Mutation Taster		=30/70	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

Other links and lift over

hg19: chr9-88193840;