9-85547131-A-G

Variant names:

• chr9-85547131-A-G
• rs763549504
• NM_001330701.2:c.3659T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001330701.2(AGTPBP1):​c.3659T>C​(p.Leu1220Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AGTPBP1 NM_001330701.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.395
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013980776).

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.3659T>C	p.Leu1220Ser	missense	Exon 26 of 26	NP_001317630.1	Q9UPW5-1
	AGTPBP1	NM_001286715.1		c.3815T>C	p.Leu1272Ser	missense	Exon 25 of 25	NP_001273644.1	J3KNS1
	AGTPBP1	NM_001286717.1		c.3695T>C	p.Leu1232Ser	missense	Exon 25 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.3659T>C	p.Leu1220Ser	missense	Exon 26 of 26	ENSP00000349592.3	Q9UPW5-1
	AGTPBP1	ENST00000376083.7	TSL:1	c.3539T>C	p.Leu1180Ser	missense	Exon 26 of 26	ENSP00000365251.3	Q9UPW5-2
	AGTPBP1	ENST00000337006.8	TSL:5	c.3815T>C	p.Leu1272Ser	missense	Exon 25 of 25	ENSP00000338512.5	J3KNS1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248802 AF XY: 0.00000743

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459624 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726204

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.00 AC: 0 AN: 44188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111242

Other (OTH) AF: 0.00 AC: 0 AN: 60276

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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	Benign	0.073
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	9.9
DANN	Benign	0.95
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.2	N
PhyloP100		0.40
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.49	N
REVEL	Benign	0.018
Sift	Benign	0.20	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.072
MutPred		0.15		Gain of phosphorylation at L1220 (P = 0.0099)
MVP		0.099
MPC		0.070
ClinPred		0.026	T
GERP RS		0.58
Varity_R		0.028
gMVP		0.12
Mutation Taster		=94/6	polymorphism

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: rs763549504; hg19: chr9-88162046;