9-85579056-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001330701.2(AGTPBP1):c.3206G>T(p.Cys1069Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000383 in 1,610,636 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: AGTPBP1 NM_001330701.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021485656).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000821 (125/152258) while in subpopulation AFR AF= 0.002 (83/41556). AF 95% confidence interval is 0.00165. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGTPBP1	NM_001330701.2	c.3206G>T	p.Cys1069Phe	missense_variant	24/26	ENST00000357081.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGTPBP1	ENST00000357081.8	c.3206G>T	p.Cys1069Phe	missense_variant	24/26	5	NM_001330701.2	P1

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 125 AN: 152140 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000364 AC: 90 AN: 247282 Hom.: 0 AF XY: 0.000299 AC XY: 40 AN XY: 133844

Gnomad AFR exome AF: 0.00151

Gnomad AMR exome AF: 0.000686

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.000668

GnomAD4 exome AF: 0.000337 AC: 492 AN: 1458378 Hom.: 0 Cov.: 30 AF XY: 0.000316 AC XY: 229 AN XY: 725506

Gnomad4 AFR exome AF: 0.00229

Gnomad4 AMR exome AF: 0.000776

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000283

Gnomad4 OTH exome AF: 0.000897

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152258 Hom.: 0 Cov.: 33 AF XY: 0.000887 AC XY: 66 AN XY: 74446

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000534 Hom.: 0

Bravo AF: 0.000963

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000354 AC: 43

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurodegeneration, childhood-onset, with cerebellar atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
Cadd	Pathogenic	27
Dann	Uncertain	0.99
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.021	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N;.;N;.
REVEL	Benign	0.10
Sift	Uncertain	0.026	D;.;D;.
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.41	B;.;P;P
Vest4		0.58
MVP		0.33
MPC		1.6
ClinPred		0.041	T
GERP RS		4.6
Varity_R		0.36
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs148724007; hg19: chr9-88193971;