rs1554699491

Variant names:

• chr9-85596450-C-A
• rs1554699491
• NM_001330701.2:c.2336-1G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-85596450-C-A
• chr9-85596450-C-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001330701.2(AGTPBP1):​c.2336-1G>T variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000714 in 1,401,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: AGTPBP1 NM_001330701.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.54
• Publications: 1 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.8, offset of 29, new splice context is: cactcatgtattcggttcAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-85596450-C-A is Pathogenic according to our data. Variant chr9-85596450-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 522816.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTPBP1	NM_001330701.2	MANE Select	c.2336-1G>T		splice_acceptor intron	N/A	NP_001317630.1
	AGTPBP1	NM_001286715.1		c.2492-1G>T		splice_acceptor intron	N/A	NP_001273644.1
	AGTPBP1	NM_001286717.1		c.2372-1G>T		splice_acceptor intron	N/A	NP_001273646.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGTPBP1	ENST00000357081.8	TSL:5 MANE Select	c.2336-1G>T		splice_acceptor intron	N/A	ENSP00000349592.3
	AGTPBP1	ENST00000376083.7	TSL:1	c.2216-1G>T		splice_acceptor intron	N/A	ENSP00000365251.3
	AGTPBP1	ENST00000337006.8	TSL:5	c.2492-1G>T		splice_acceptor intron	N/A	ENSP00000338512.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1401462 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 696512

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31350

American (AMR) AF: 0.00 AC: 0 AN: 34632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24134

East Asian (EAS) AF: 0.00 AC: 0 AN: 38704

South Asian (SAS) AF: 0.00 AC: 0 AN: 76188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5510

European-Non Finnish (NFE) AF: 9.23e-7 AC: 1 AN: 1083442

Other (OTH) AF: 0.00 AC: 0 AN: 57518

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 11, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

AGTPBP1-related disorder Pathogenic:1

Jan 05, 2017

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This individual has been reported in PMID: 30420557.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		5.5
GERP RS		5.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.88		Position offset: -30
DS_AL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554699491; hg19: chr9-88211365;